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Emily Whitehead:

Emily Whitehead

Warriors come in all shapes and sizes. Take for example Emily Whitehead, as fresh-faced a 16-year-old as has ever graced the planet. Her eyes nearly sparkle with intellectual curiosity and dreams for a fulfilling future. But Emily is not a typical teen. She is the first pediatric patient in the world to receive CAR T-cell therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). She is a singular figure in the annals of medicine. She is a soldier on the front lines of the war on cancer. And like the shot heard round the world, her personal medical assault sparked a revolution in cancer care that continues to power forward.

It has been 10 years since the only child of Thomas and Kari Whitehead of Philipsburg, PA, received an infusion of CAR T cells at the hands of a collaborative medical team from the Children's Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania. That team included, among others, luminary CAR T-cell therapy pioneer, Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and Director of the Center for Cellular Immunotherapies at Penn's Perelman School of Medicine; as well as Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine (at that time, Director of the Cancer Immunotherapy Program at CHOP) and now Section Chief for Cell Therapy and Transplant at the hospital. He had been working with June on cell therapies since 2000.

Tremendous progress has flowedgushedfrom the effort to save Emily Whitehead; many more lives have been saved around the globe since that fatefulyet nearly fatalundertaking. While all the progress that has come from this story must be our ultimate theme, it cannot be fully appreciated without knowing how it came to be.

In 2010, Emily, then 5 years old, went from a being a healthy youngster one day, to a child diagnosed with ALL. Chemotherapy typically works well in pediatric ALL patients; Emily was one of the exceptions. After 2 years of intermittent chemotherapy, she continued to relapse. And when a bone marrow transplant seemed the only hope left, her disease was out of control and the treatment just wasn't possible. The Whiteheads were told by her medical team in Hershey, PA, nothing more could be done. They were instructed to take Emily home where she could die peacefully, surrounded by family.

But peaceful surrender didn't interest the Whiteheads; they rejected any version of giving up. It ran contrary to Tom Whitehead's vision of her recovery, something he said was revealed to him in the whispers. He saw, in a prophetic whispering dream, that Emily would be treated in Philadelphia. More importantly, he saw she would survive. It is as if it happened yesterday, said Tom, remembering how unrelentingly he called doctors at CHOP and said, We're coming there, no matter what you can or cannot do. We're not letting it end like this.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world.Stephan Grupp, MD, PhD

A combination of persistence and perfect timing provided the magic bullet. It was just the day before that CHOP received approval to treat their first pediatric relapsed/refractory ALL patient with CAR T cells in a trial. And standing right there, on the threshold of history, was that deathly sick little girl named Emily.

At that time, only a scant few terminal adult patients had ever received the treatment, which is now FDA-approved as tisagenlecleucel and developed in cooperation with CHOP and the University of Pennsylvania. When three adults were treated, two experienced quick and complete remission of their cancers. Could CAR T-cell therapy perform a miracle for Emily? A lot would ride on the answer.

On March 1, 2012, Emily was transferred to CHOP and a few days later an apheresis catheter was placed in her neck; her T cells were extracted and sent to a lab. Emily received more chemotherapy, which knocked out her existing immune system, and she was kept in isolation for 6 weeks. Waiting.

Finally, over 3 days in April, Emily's re-engineered T cells, weaponized with chimeric antigen receptors, were infused back into her weakening body. But Emily did not rise like a Phoenix from the ashes of ALL. Instead, she sunk into the feverish fire of cytokine release syndrome (CRS), and experienced a worse-than-anticipated reaction. The hope for a swift victory seemed to be disappearing.

I can still see Emily's blood pressure dropping down to 53/29, her fever going up to 105F, her body swelling beyond recognition, her struggle to breathe, said Tom, of the most nightmarish period of his life. Doctors induced a coma, and Emily was put on a ventilator. For 14 days, her death seemed imminent. Doctors told us Emily had a one in a thousand chance of surviving, said Tom. They said she could die at any moment. But she didn't.

Medical team members who fought alongside the young patient are unwavering heroes in Emily's story. But at the time of her massive struggle, they too were exhausted and battle-scarred, descending into the quicksand of what could have been a failing trial, grasping for some life-saving branch of stability. They knew if CRS could be overcome, the CAR T cells might work a miracle as they had done for those earlier adult patients. But the CRS was severe. There was no obvious antidote; time was running out.

I recall Dr. June saying he believed Emily was past the point where she could come back and recover, said her father. And he said if she didn't turn around, this whole immunotherapy revolution would be over.

The Whiteheads enjoy Penn State football games not far from their hometown. The family has often taken part in Penn State's THON, a 48-hour dance marathon that raises funds for childhood cancer.

June confirmed to Oncology Times that he and Grupp believed Emily would not survive the night. It was mentioned to the Whiteheads that perhaps they should just concentrate on comfort care measures and stop all the ICU interventions, he recalled. I believed she was going to die on the trial due to all the toxicity. I even drafted a letter to our provost to give a heads up.

When the first patient in a trial dies, that's called a Grade 5 toxicity, June noted. That closes the trial as well. It goes right into the trash bin and you have to start all over again. But fortunately, that letter never left my outbox. We decided to continue one more day, and an amazing event happened.

Grupp, offering context to the mysterious amazing event, said it was clear that Emily's extreme CRS was caused by the infusion of cells that he himself had placed in her fragile body. He said he felt an enormous sense of responsibility and incredible urgency as he watched the child struggle to live.

It was not until the CHOP/Penn team received results from a test profiling cytokines in Emily's body that a new flicker of hope sparked. Though Emily had many cytokine abnormalities, the one most strikingly abnormal, interleukin-6 (IL-6), caught the team's attention. It is not made by T cells, and should not have been part of the critical mix. Though there were very few cytokines that had drugs to target them individually, IL-6 was one that did. So the doctors decided to repurpose tocilizumab, an arthritis drug, as a last-ditch effort at saving their young patient.

We treated Emily with tocilizumab out of desperation, June admitted. Steve [Grupp] has told me that when he went to the ICU with tocilizumab as a rescue attempt for CRS, the ICU docs called him a cowboy. The ICU docs had given up hope for Emily. But she turned aroundunbelievably rapidly. Today, tocilizumab is the standard of care for CRS, and the only drug approved by the FDA for that complication. Emily's recovery was huge for the entire field.

Grupp reflected on the immensity of the moment. If things had gone differently, if Emily had experienced fatal toxicity, it would have been devastating to her family and to the medical team. And it might have ended the whole research endeavor. It would have set us back years and years. The impact that Emily and her family had on the field is nothing short of transformational, he declared.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world, Grupp noted. And, if not for Emily, we wouldn't be in the position we are in todaywith five FDA-approved [CAR T-cell] products: four for adults and one for kids. And I think it also important to point out that the very first CAR-T approval, thanks to Emily, was in pediatric ALL.

June noted that between 2010 and the time of Emily's treatment in 2012, My work was running like a shoestring operation. I had to fire people because I couldn't get grants to support the infrastructure of the research. It was thought there was no way beyond an academic enterprise to actually make customized T cells, then mail and deliver them worldwide, he recalled.

But then everything changed. We experienced that initial success; it was totally exciting. It was a career-defining moment and the culmination of decades of research. It led to a lot of recognition, both for my contribution and for the team here at the University of Pennsylvania and at CHOP.

Today, hundreds of pharmaceutical and biotech companies are developing innovations. Hundreds of labs are making next-generation approaches to improve in this area, June noted. Today, I'm a kid in a candy shop because all kinds of things are happening. We have funding thanks to the amazing momentum from Emily. She literally changed the landscape of modern cancer therapy.

Grupp said the continuing CAR T-cell program at CHOP offers evidence of success in a broad perspective. There are two things to look at, he offered. The first is how well patients do with their therapy in terms of getting into remission. A month after getting their cells, are they in remission or not? A study with just CHOP patients showed that more than 90 percent met that bar (N Engl J Med 2014; doi: 10.1056/NEJMoa1407222). Worldwide, the numbers appear to be in the 80 percent range (N Engl J Med 2018; doi: 10.1056/NEJMoa1709866). So, I would say it is a highly successful therapy.

We now have trials using different cell types, like natural killer cells, monocytes, and stem cells, noted Carl June, MD, at Penn's Perelman School of Medicine. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer.

The other big question, Grupp noted: How long does remission last? We are probably looking at about 50 percent of patients remaining in remission long-term, which is to say years after the infusion. The farther out we go, the fewer patients there are to look at because it just started with Emily in 2012, reminded Grupp. We have Emily now 10 years out, and other patients who are at 5, 6, 7, 8 years out, but most were treated more recently than that. We need to follow them longer.

June said registries of patients treated with CAR T-cell therapy are being kept worldwide by various groups, including the FDA. CAR T-cell therapy happened fastest in the U.S., but it's gained traction in Japan, Europe, Australia, and they all have databases. The U.S. database for CAR T cells will probably be the best that exists, because the FDA requires people treated continue follow-up for at least 15 years, he explained.

This will provide important information about any long-term complications, and the relapse rate. If patients do get cancer again, will it be a new one or related to the first one we treated? We will follow the outcomes, he noted. Clinicians are teaching us a lot about how to use the informationat what stage of the disease the therapy is best used, and which patients are most likely to respond. This can move us forward.

June mentioned that Grupp is collaborating with the Children's Oncology Group ALL Committee led by Mignon Loh, MD, at the University of California in San Francisco.

They are conducting a national trial to explore using CAR T cells as a frontline therapy in newly diagnosed patients, he detailed. Emily was treated when she had pounds and pounds of leukemia in her body; ideally we don't want to wait so long. There are a lot of reasons to believe it would work as a frontline therapy and spare patients all the complications of previous chemotherapy and/or radiation. The good news is that the clinical trial is under way, and I suspect we may know the answer within 2 years.

The only true measure of success in Emily's case is the state of her health. When asked if she is considered cured, June said, All we can do is a lot of prognostication. We know with other therapies in leukemia, the most similar being bone marrow transplants, if you go 5 years without relapsing, basically you are considered cured. We don't know with CAR T cells because Emily is the first one. We have no other history. But she's at a decade now, and in lab data we cannot find any leukemia in her. So by all of the evidence we haveand by looking in the magic eight ballI believe Emily is cured.

One might think that going through such a battle for life would be enough for any one person, any one family. But for Emily and her parents, her survival was just the beginning of a larger assault. All of them saw the experience as a way to provide interest in continuing research, education for patients as well as physicians, and an extension of hope to other patients about to succumb to a cancerous enemy.

Tom thought back to one particular occasion, all those years ago, when Emily finally slept peacefully through the night in her hospital bed. I should have felt nothing but relief, but I heard a mother crying in the hallway. Her child, who has been in the room next door, had died that morning, he recalled. I am constantly reminded of how fortunate we are. There are so many parents fighting for their children who do not have a good outcome.

As soon as Emily regained her strength and resumed normal childhood activities, the family began travelling with members of the medical team, joining in presentations at meetings and conferences throughout the world. They wanted to give a human face to the potential of CAR T-cell therapy, and as such they willingly became a powerful tool to raise understanding and essential research dollars. In 2016, the Whiteheads founded the Emily Whitehead Foundation (www.emilywhiteheadfoundation.org) ...to help fund research for new, less toxic pediatric treatments, and to give other families hope.

We decided to hold what we called the Believe Ball in 2017. We asked lots of companies to sponsor a child who had received CAR T-cell treatment to come with their family to the ball at no cost to them. Each company's representative would be seated with the child and family they sponsored, and would meet the doctors and scientists involved in the research, as well as members of industry and pharma, to see exactly where research dollars are going. We implored these companies to move the cancer revolution forward with sponsorship. When it all shook out, we had around 35 CAR T-cell families together for the first time, said Tom.

He noted proudly that since the foundation's debut, donations have been consistent and now have totaled an impressive $1.5 million.

When the Emily Whitehead Foundation had a virtual gala recently, it awarded a $50,000 grantthe Nicole Gularte Fight for Cures Ambassador Awardto a young researcher working to get another trial started. The award is named for a woman who found her way to CAR T-cell trials at Penn through the Whitehead Foundation. The treatment extended her life by 5 years during which time Gularte became an advocate for other cancer patients, travelled with the Whiteheads, and made personal appearances whenever she thought she could be of help or inspiration. Eventually, she would relapse and succumb, but she assured Tom Whitehead, These were 5 of the best years of my life. I think my time here on Earth was meant to help cancer research move forward.'

While raising funds for progress is important, the Whiteheads' work is not just about bringing in money. It's also about education.

We want to send a message to all oncologists; they need to be more informed about these emerging treatments when their patients ask for help, Tom noted. In the beginning of CAR T-cell therapy, a lot of doctors were against it. It's hard to believe, but some still are, though not as much. We need more education so that oncologists give patients a chance to get to big research hospitals for cutting-edge treatments before everything else has failed.

June said he regularly interacts with patients Tom or the foundation refer to him. Such unawareness happens with all new therapies, he noted. The people most familiar with them are at academic medical centers. But only about 10 percent of patients actually go to academic centers, the rest are in community centers where newer therapies take much longer to roll out, he explained.

So much of Emily's life has been chronicled through the eyes of observers. But since her watershed medical intervention, she has grown into a well-travelled, articulate young woman who talks easily about her life. I used to let my father do all the talking, but I am finding my own voice now, she said, having granted an interview to Oncology Times.

I'm currently 16 years old and I'm a junior at high school. Just like when I was younger, cows are my favorite animals, she offered with a laugh. I still love playing with our chihuahua, Luna. In school, I love my young adult literature class because I really like reading. Besides that, I like art and film. And I'm in really good health today.

She mentioned her health casually, almost as an afterthought. I really don't have any memory of my treatment at this point, she revealed, but, the experiences that I've had since then have really shaped who I am. Traveling is a huge part of my life now and something I look forward to. We've been to conferences at a lot of distant places. I'm so grateful that I get to travel with my family and make these memories that I will have forever, while still being able to advocate for less toxic treatment options and raising money for cancer research. All of that is really important to me.

Reminded that she has already obtained fame as pediatric patient No. 1 for CAR T-cell therapy, Emily considered her status for a moment then commented, I don't really like to base the progress of the therapy on my story and what I went through. Instead, I like to take my experience and use it to advocate for all patients so that what happened to me does not have to be repeated and endured by another family. My hope is that CAR T-cell therapy will become a frontline treatment option and be readily available, so pediatric patients can get back to a normal life as soon as possible. I want to tell people if conventional treatments do not work, other options do exist. Overall, I am grateful that I can encourage others to keep fighting. That's the main thing; I am grateful.

After a brief pause, Emily continued, I always tell oncologists and scientists that the work they are doing is truly saving children's lives. It allows these kids to grow up, be with their friends and families, take vacations, play with their dogs, and someday go to college, just like me. They are not only saving patients' lives, they are saving families. The work they do does not go unnoticed or unappreciated. Again, I am really so grateful.

Appreciation is a two-way street, and June said he and his team appreciate and draw inspiration from Emily on a daily basis. Her picture hangs on the wall of our manufacturing center, June stated. Some of the technicians who were in high school when Emily was infused are now manufacturing CAR T cells. They learned so much from Emily's experience; she continues to be a big motivator. She's helped my team galvanize and see that the work can really benefit people.

Grupp said the success that is embodied in Emily Whitehead has spurred additional successes, and new inroads in CAR T-cell therapy. There are more applications now, especially in other blood cancerslymphoma and myeloma, in addition to leukemia. We've seen a lot of expansion there.

He noted a national trial is under way for an FDA-approved therapy called idecabtagene vicleucel, which can benefit multiple myeloma patients. All other CAR Ts target the same target, CD19. But this goes after an entirely different target, BCMA. The fact that we now have approval in something that isn't aimed at CD19 is very exciting. And there are others coming right behind it.

The field also has seen further expansion ...into adults being treated safely, because initially there was concern that these drug therapies were too powerful for safe treatment in older adults, detailed Grupp. Now we know that is clearly not the case, and that is great news, particularly because multiple myeloma most often occurs in people over 60.

The use of CAR T cells in solid tumors continues to be challenging, although Grupp noted, We have certainly seen hints of patients with solid tumors having major responses and going into remission with CAR T cells. It is still a small handful of patients, so we haven't perfected the recipe for solid tumors yet. But I am absolutely confident we will have the answers in a very short numberperhaps 2-4of years.

June said, since Emily's infusion, CAR T cells have matured and gotten better. There are many ways that has happened, he informed. We have different kinds of CAR designs to improve and increase the response rates, to decrease the CRS, or to target other kinds of bone marrow cancers. One that is not curable with a lot of therapies is acute myeloid leukemia (AML), so we have a huge group at Penn and CHOP working on AML specifically. And there is the whole field of solid cancer; we have teams working on pancreatic, prostate, breast, brain, and lung cancer now.

In addition to targeting different types of cancer, June said contemporary research is also exploring the use of different types of cells. Our initial CAR T trial used T cells, and that is what all the FDA-approved CARs are. But we now have trials using different cell types, like natural killer cells, monocytes, and stem cells. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer, not just leukemia and lymphoma.

Is this the beginning of the end of cancer? Is this that Holy Grail called a cure to cancer? It's a question June has pondered.

Some people do think that, he answered. They believe the immune system is the solution. And that's a huge statement. President Biden has made a big investment in this work, with the Cancer Moonshot. He's accelerated this research at the federal level. But we just don't know how long it is going to take. Fortunately, a lot of good minds are working hard to make an end to cancer a reality.

As the battle grinds on, June said he applies something he's learned over time, with reinforcement from Tom and Kari Whitehead. They were bulldogs. When it came to getting treatment for Emily, they just wouldn't take no for an answer. They demonstrated the importance of never giving up. That's what happened; they would not surrender. I think that is why Emily is alive today.

Valerie Neff Newitt is a contributing writer.

The Emily Whitehead Foundation and the Whitehead family take extraordinary advantage of a variety of media to reach patients and physicians and optimize educational opportunities.

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The Incredible Story of Emily Whitehead & CAR T-Cell Therapy : Oncology Times - LWW Journals

March 18, 2022

ChristianaCares Helen F. Graham Cancer Center & Research Institute is advancing its historic partnership with the Ellen and Ronald Caplan Cancer Center of The Wistar Institute in Philadelphia, Pennsylvania, with three new research projects under way.

The new research projects consist of a population health study targeting triple negative breast cancer. Other projects focus on a new therapeutic target for epithelial ovarian cancer, the most lethal gynecologic cancer in the developed world, and the development of mini organs derived from stem cells.

Delaware has one of the highest incidence rates of triple-negative breast cancer in the United States. This highly aggressive cancer has few treatment options, because the cells test negative for three known treatment targets estrogen, progesterone and HER2 protein receptors.

Working with patient data from the Graham Cancer Center, researchers are investigating potential contributing factors such as diet, alcohol use and genetic variants among women, and the effects of these on cancer metabolism. The team will also examine spatial relationships between cancer hot spots geographic areas with a higher-than-expected prevalence and modifiable risk factors.

Key resources for the study are blood and tissue samples from the Graham Cancer Centers Tissue Procurement Center and its statewide High-Risk Family Cancer Registry.

The research team will be led by Director of Population Health Research at ChristianaCare Scott Siegel, Ph.D., and Lead Research Scientist Jennifer Sims Mourtada, Ph.D., at the Graham Cancer Centers Cawley Center for Translational Cancer Research (CTCR). They will join Zachary Schug, Ph.D., at Wistars Molecular and Cellular Oncogenesis Program.

The latest study supported by the Graham Cancer Centers Tissue Procurement Program targets KAT6A expression as a novel therapy for ovarian cancer caused by a specific genetic mutation, called PP2R1A.

Epithelial ovarian cancer is the most common form of ovarian cancer and the leading cause of gynecologic cancer deaths in the United States.

Chemoresistance to currently available platinum-based drugs like cisplatin represents a major treatment challenge, as more than 50 percent of affected women ultimately relapse and die from this disease.

Wistars Rugang Zhang, Ph.D., leader of the Immunology, Microenvironment and Metastases Program, is focused on developing novel therapeutics for subtypes of ovarian cancer that currently have no effective therapies and on improving the current standard of care.

Dr. Zhangs previous work suggests that KAT6A signaling plays a critical role in ovarian cancer progression. Targeting this signaling pathway could be an effective strategy for treating ovarian cancer.

Working with Dr. Zhang on this project are Graham Cancer Center gynecologic oncologists Mark Cadungog, M.D., director of Robotic Surgery, and Sudeshna Chatterjee-Paer, M.D., and Cawley CTCRs Stephanie Jean, M.D., director of Gynecologic Oncology Research. Also collaborating with the team is Wistars Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program.

Dr. Sims-Mourtada at the Cawley CTCR will lead a new program to culture organ-specific tissue from stem cells that could change the way diseases are studied and treated.

These so called mini organs or organoids are three-dimensional tissue cultures grown in the lab that replicate the complexity and functions of a specific tissue or organ found in the body.

Organoids offer scientists a better model for how drugs and other therapeutics might interact with a patients particular type of tumor, opening new avenues for precision medicine.

The ability to grow each patients tumor in a three-dimensional organoid along with our capability to create patient-derived xenograft or animal models as part of our PDX core, will allow us to fully capture the effects of genetic as well as gene altering behavioral and environmental influences that are lacking in current research models, said Dr. Sims-Mourtada.

Our collaboration with Wistar to build these programs raises our clinical platform to the next level for studying new cancer biomarkers and treatments.

The Graham Cancer Center made history when it signed a first-of-its-kind agreement in 2011 with The Wistar Institute, pairing a National Cancer Institute, NCI-designated basic research institution with a community cancer center that is also an NCI Community Oncology Research Program (NCORP).

Our partnership with Wistar has attracted national recognition as a model of collaboration that leverages cutting-edge research to benefit cancer prevention and therapy statewide, says Nicholas J. Petrelli, M.D., Bank of America endowed medical director of ChristianaCares Helen F. Graham Cancer Center and Research Institute.

With Wistar, our productive collaborations over the last decade continue to drive discovery research toward clinical trials to benefit patients here at the Graham Cancer Center and in communities everywhere.

The Graham Center has been an ideal partner in our mission, said Dario C. Altieri, M.D., Wistar president and CEO and director of the Ellen and Ronald Caplan Cancer Center. Our scientists at Wistar have access to clinically-annotated primary patient specimens of the highest quality.

As the majority of patients at the Graham Cancer Center are treatment nave, this collaboration affords an opportunity to conduct unique, high impact mechanistic and correlative studies that will ultimately advance important scientific discoveries that hopefully will lead to better cancer therapies.

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ChristianaCare and The Wistar Institute Advance Partnership With New Cancer Research Strategies - ChristianaCare News

Within Penn States College of Medicine, three female researchers won Whitaker Centers Women of Impact: Celebrating Women in STEM Awards for their advancement in the field, which Elizabeth Proctor said was an honor.

Proctor said she received the Game Changer award under the Whitaker Centers Women of Impact in September 2021 for her research on Alzheimer's disease.

I was really honored and happy that people saw this worth in my work, Proctor, assistant professor of neurosurgery, pharmacology, biomedical engineering, and engineering science and mechanics, said.

For Proctor, shes really passionate about studying Alzheimers disease and the different moving pieces in the disease.

Proctor received her bachelor's degree from Purdue University and Ph.D. in biophysics from the University of North Carolina at Chapel Hill, and then she held a postdoctoral position at the Massachusetts Institute of Technology.

One reason Proctor developed an interest in studying Alzheimers disease was watching individuals in her family who were personally affected.

It is so common, and we have no cure, Proctor said. Its a horrible thing to lose yourself, and that is what Alzheimers takes from people.

Proctor said she also saw a gap that somebody with her skill set could fill in the research and her goal became to figure out how all the pieces fit together.

While completely respecting all the community that has come before, I thought there is this one piece that maybe I could help that I haven't seen anyone else doing, and I am uniquely suited to do it, Proctor said.

She said she wanted to learn what causes patients to present cognitive deficits, memory impairment and all these things that drive people to go to a doctors office and say, I am sick, I need help.

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What we are trying to do is make this overall map and try to understand how we could affect the entire disease and actually try to fix it in a way that would address all these issues and ultimately make cognition better, Proctor said.

Proctor said in her research lab, she tries to measure at the molecular level different processes that are dysregulated in the disease, using everything from cells to organoids to animals.

We have not done human samples yet, but we hope to in the future, Proctor said. And we try to use all these different systems to untangle all of the processes that are being dysregulated.

Within her research, Proctor said shes trying to come in and do something that has never been done before and potentially make a very large impact on the way the field understands science which is why she believes she won the award.

I am trying to unite people who do more molecular and cellular work with people who do my physiological research, Proctor said. In the way that I have been trying to do this with computational science, it hasnt been done before.

While Proctor said she wont cure Alzheimers or completely change the field herself, rather, she intends to contribute to the advancement of understanding the disease.

I am not coming in and trying to rescue anything, but I think there are things that I could do that arent being done right now that maybe I am uniquely suited for, Proctor said.

Dr. Shou Ling Leong was also a recipient of the Game Changer award as a result of helping create curriculum for the three-year accelerated medical pathway.

Leong, assistant dean for pathways innovation in the College of Medicine, associate vice chair for education, director of longitudinal and 3+ accelerated pathways, and professor of family and community medicine, said she was thrilled to receive the award.

You never know about these things, Leong said. When you get nominated, you feel that people value what you have done and recognize the impact you have made, but when it is finally validated, it's a joy.

Leong said she wears many hats, such as clinical work, education and research, but what she loves the most is to innovate and develop new things.

She develops new programs, one being the three-year program, and she also conducts assessments and research to make sure the programs are impactful and have measurable outcomes.

For example, with the three-year program, we have done big studies to make sure that students indeed get a good education, Leong said. So after they graduate, they have the competency to be excellent doctors but also satisfied with their curriculum and not stressed and burnt out.

Inspiration for the three-year program came primarily from the news, Leong said, because there has been talk [in the media] that we dont have enough physicians particularly primary care physicians.

We know that students are graduating with huge amounts of debt, so I want to address those things, Leong said. It became clear to me that by having a three-year program, it would address both of those issues and others, too.

By graduating a year early, students save quite a bit of money and in the process, help to address the physician shortage, Leong said.

Leong said the three-year program has really made a difference in medical education and reframed how we look at medical education which is why she believes she was a recipient of the award.

I feel very proud and very happy to have gotten the award, Leong said.

Jennifer Moss had been named the Women to Watch Class of 2021 under the Whitaker Centers Women of Impact, which is given to a scientist in their early career.

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Moss, assistant professor in the department of family and community medicine, and the department of public health sciences at Penn State, said she conducts research on the impact of geography and community factors on cancer prevention and cancer outcome.

Trying to identify what it is about certain communities particularly rural communities that make them more susceptible to elevated rates of cancer incidents and cancer mortality is the center of her research, Moss said.

What shes found is a complex web of factors that influence what makes people more or less likely to engage in behaviors that prevent cancer, such as vaccination, physical activity and screening behaviors, and how they translate into different incidents and mortality, Moss said.

Moss was born in a rural community in Texas and moved around a lot, which is what prompted her to research how cancer affects various populations.

The difference in life expectancy and cancer rates for someone where I was born versus where I got my training were really stark, and it prompted me to think about what I could do with training in behavioral science and social epidemiology in order to reduce the higher rates of cancer we see, and that is what I try and do with my work identify the causes of these disparities and solutions, ways that we can get health care services to people living in rural communities, Moss said.

Moss has been working with small clinics in Pennsylvania to evaluate how feasible it is for patients, particularly in rural and isolated communities, to use at-home tests for screening of cancer so they dont have to travel to a doctors office to get screened.

It really empowers patients in rural communities to get tested, and if they do have cancer, we can identify it and diagnose it earlier, Moss said.

Moss said she was very thrilled to receive the award.

I was nominated by the chair of my department, who has always been very supportive of my work and my career, so it was great to get that recognition from the community and join this sort of cohort of women who received awards from the Whitaker Center, Moss said.

The Whitaker Center continues to do a lot of work to support women in science, according to Moss.

Not just for us who are professionals but also for girls and young women who are still learning about the potential careers in science.

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CRANFORD, N.J., Oct. 25, 2021 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products with a focus on oncology, anti-infective products in adjunct cancer care, unique prescription products, and stem cell therapies, today announced that it will host a key opinion leader (KOL) webinar on the compelling need to salvage central venous catheters in patients with central line associated blood stream infections (CLABSI) on Thursday, November 11, 2021 at 11:30am Eastern Time.

The webinar will feature a presentation by leading infectious disease experts Issam Raad, MD, University of Texas MD Anderson Cancer Center and Mark Rupp, MD, University of Nebraska Medical Center. Dr. Raad will discuss the unmet medical need in the treatment of patients with infected central venous catheters (CVCs), and the potential of Citius's Mino-Lok® treatment to salvage infected catheters. Dr. Rupp will discuss the effect of the COVID-19 Pandemic on CLABSI rates in acute care facilities. Citius Pharmaceuticals' Chief Medical Officer, Myron Czuczman, MD, will provide an update on the company's Mino-Lok® program. Drs. Raad, Rupp and Czuczman will be available to answer questions following the formal presentations.

Pre-registration for the webcast is required.

Date

Thursday, November 11, 2021

Time

11:30 a.m. ET

Registration link

To participate, please register prior to the event date using this link

Webcast (live and archive)

Available at http://www.citiuspharma.com in the "Events" section

Q&A

Questions may be submitted in advance using this link

Featured Speakers

Issam Raad, MD, FACP, FIDSA, FSHEA

Dr. Issam Raad, G. H. Fletcher Distinguished Chair & Professor, Department of Infectious Diseases, Infection Control and Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, is considered one of the leading experts in the field of health care related infections and infections in cancer on a worldwide basis. During his more than 25 years at MD Anderson, Dr. Raad has made numerous outstanding clinical research contributions that have led to significant improvements in controlling life-threatening infections for patients with cancer and other serious illnesses throughout the world. His research includes development of innovative antimicrobial central venous catheters and devices that have reduced the risk of bloodstream infections worldwide more than 12-fold. In the most recent CDC Guidelines (2011), his innovations, including the antimicrobial catheters and maximal sterile barrier, have been recommended at the highest level (Category 1A) for the prevention of health care associated bloodstream infections which have become the standard of care.

Mark Rupp, MD

Dr. Mark Rupp, is Chief of the Division of Infectious Diseases and Professor in the Department of Internal Medicine, Section of Infectious Diseases at the University of Nebraska Medical Center. He is the Medical Director of The Nebraska Medical Center Department of Healthcare Epidemiology and Co-Director of the Antimicrobial Stewardship Program. He is a Diplomate, American Board of Internal Medicine, and in the subspecialty area of Infectious Diseases. Dr. Rupp is also a Fellow of the Society for Hospital Epidemiology of America (SHEA), American College of Physicians (ACP), and the Infectious Diseases Society of America (IDSA). He is a Past-President of SHEA and is a past-president of ASM Division L (Infection Control/Hospital Epidemiology). Dr. Rupp has served as a consultant for the US Food and Drug Administration as well as the Centers for Disease Control and Prevention.

Myron Czuczman, MD, Citius Pharmaceuticals Chief Medical Officer

Dr. Czuczman is an experienced physician-scientist, academic oncologist, and pharmaceutical executive with decades of experience in strategic design, implementation, and oversight for the global development of novel therapeutics for hematologic malignancies. Dr. Czuczman joined Citius from Celgene where he was Vice President, Global Clinical Research and Development, Therapeutic Area Head of Lymphoma/CLL. In this role, Dr. Czuczman managed a global team of physicians and scientists responsible for cross-functional development of compounds from proof-of-principle to worldwide registration. Prior to his career in pharma, Dr. Czuczman practiced medicine for over two decades at Roswell Park Cancer Institute, an NCI-designated comprehensive cancer center in Buffalo, NY, where he served as chief of the Lymphoma/Myeloma Service and head of the Lymphoma Translational Research Laboratory. In addition to his extensive publications record, membership and leadership roles on national and international research organizations, and consulting and advisory to dozens of pharma companies, Dr. Czuczman also attained the positions of tenured Professor of Medicine at the State University of New York at Buffalo School of Medicine and Biomedical Sciences and Professor of Oncology at Roswell Park Comprehensive Cancer Center.

Dr. Czuczman received his medical degree from Pennsylvania State University College of Medicine after graduating magna cum laude in biochemistry from the University of Pittsburgh. He completed his Internal Medicine residency training at Weill Cornell North Shore University/MSKCC Program, followed by Medical Oncology/Hematology fellowship training at Memorial Sloan-Kettering Cancer Center in New York City.

About Citius Pharmaceuticals, Inc.

Citius is a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products, with a focus on oncology, anti-infectives in adjunct cancer care, unique prescription products, and stem cell therapies. The Company has two late-stage product candidates, Mino-Lok®, an antibiotic lock solution for the treatment of patients with catheter-related bloodstream infections (CRBSIs), which is currently enrolling patients in a Phase 3 Pivotal superiority trial, and I/ONTAK (E7777), a novel IL-2R immunotherapy for an initial indication in cutaneous T-cell lymphoma (CTCL), which has completed enrollment in its Pivotal Phase 3 trial. Mino-Lok® was granted Fast Track designation by the U.S. Food and Drug Administration (FDA). I/ONTAK has received orphan drug designation by the FDA for the treatment of CTCL and peripheral T-cell lymphoma (PTCL). Through its subsidiary, NoveCite, Inc., Citius is developing a novel proprietary mesenchymal stem cell treatment derived from induced pluripotent stem cells (iPSCs) for acute respiratory conditions, with a near-term focus on acute respiratory distress syndrome (ARDS) associated with COVID-19. For more information, please visit http://www.citiuspharma.com.

Safe Harbor

This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated are: risks relating to the results of research and development activities, including those from existing and new pipeline assets; uncertainties relating to preclinical and clinical testing; our need for substantial additional funds; the early stage of products under development; our dependence on third-party suppliers; our ability to successfully undertake and complete clinical trials and the results from those trials for our product candidates; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our ability to commercialize our products if approved by the FDA; market and other conditions; risks related to our growth strategy; patent and intellectual property matters; our ability to attract, integrate, and retain key personnel; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; our ability to procure cGMP commercial-scale supply; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by Covid-19. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings which are available on the SEC's website at http://www.sec.gov, including in our Annual Report on Form 10-K for the year ended September 30, 2020, filed with the SEC on December 16, 2020 and updated by our subsequent filings with the SEC. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Investor Relations for Citius Pharmaceuticals:

Ilanit Allen Vice President, Investor Relations and Corporate Communications T: 908-967-6677 x113 E: ir@citiuspharma.com

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Citius Pharmaceuticals to Host Key Opinion Leader Webcast on the Compelling Need to Salvage Central Venous Catheters in CLABSI Patients - Stockhouse

News Release

Wednesday, October 27, 2021

The National Institutes of Health, U.S. Food and Drug Administration, 10 pharmaceutical companies and five non-profit organizations have partnered to accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease. While there are approximately 7,000 rare diseases, only two heritable diseases currently have FDA-approved gene therapies. The newly launched Bespoke Gene Therapy Consortium (BGTC), part of the NIH Accelerating Medicines Partnership (AMP) program and project-managed by the Foundation for the National Institutes of Health (FNIH), aims to optimize and streamline the gene therapy development process to help fill the unmet medical needs of people with rare diseases.

Most rare diseases are caused by a defect in a single gene that could potentially be targeted with a customized or bespoke therapy that corrects or replaces the defective gene, said NIH Director Francis S. Collins, M.D., Ph.D. There are now significant opportunities to improve the complex development process for gene therapies that would accelerate scientific progress and, most importantly, provide benefit to patients by increasing the number of effective gene therapies.

A single rare disease affects small numbers of people, but rare diseases collectively affect millions. Most rare inherited diseases stem from a specific gene mutation that is already known, making gene therapy a promising therapeutic approach. However, gene therapy development for rare diseases is highly complex, time consuming and expensive. Moreover, the development process is stymied by limited access to tools and technologies, lack of standards across the field, and a one-disease-at-a-time approach to therapeutic development. A standardized therapeutic development model that includes a common gene delivery technology (a vector) could allow for a more efficient approach to specific gene therapies, saving time and cost.

Rare diseases affect 25 to 30 million Americans, but because any given rare disorder affects so few patients, companies often are reluctant or unable to invest the years of research and millions of dollars necessary to develop, test and bring individualized gene therapy treatments for a single disease to market, said Joni L. Rutter, Ph.D., acting director of NIHs National Center for Advancing Translational Sciences (NCATS). The BGTC aims to make it easier, faster and less expensive to pursue bespoke gene therapies in order to incentivize more companies to invest in this space and bring treatments to patients.

By leveraging on experience with a platform technology and by standardizing processes, gene therapy product development can be accelerated to allow more timely access to promising new therapies for patients who need them most, said Peter Marks, M.D., Ph.D., director of FDAs Center for Biologics Evaluation and Research. FDA is committed to developing a regulatory paradigm that can advance gene therapies to meet the needs of patients with rare diseases.

A primary aim of BGTC is to improve understanding of the basic biology of a common gene delivery vector known as the adeno-associated virus (AAV). BGTC researchers will examine the biological and mechanistic steps involved in AAV vector production, vector delivery of genes into human cells and how therapeutic genes are activated in target cells. These results will provide important information for improving the efficiency of vector manufacturing and enhancing the overall therapeutic benefit of AAV gene therapy.

To improve and accelerate gene and vector manufacturing and production processes, the BGTC program will develop a standard set of analytic tests to apply to the manufacture of viral vectors made by consortium researchers. Such tests could be broadly applicable to different manufacturing methods and make the process of developing gene therapies for very rare conditions much more efficient.

A clinical component of BGTC-funded research will support between four and six clinical trials, each focused on a different rare disease. These diseases are expected to be rare, single-gene diseases withno gene therapies or commercial programs in development and that already have substantial groundwork in place to rapidly initiate preclinical and clinical studies. The trials will employ different types of AAV vectors that have been used before in clinical trials. For these trials, the BGTC will aim to shorten the path from studies in animal models of disease to human clinical trials.

The BGTC also will explore methods to streamline regulatory requirements and processes for the FDA approval of safe and effective gene therapies, including developing standardized approaches to preclinical testing (e.g., toxicology studies).

NIH and private partners will contribute approximately $76 million over five years to support BGTC-funded projects. This includes about $39.5 million from the participating NIH institutes and centers, pending availability of funds. NCATS, which developed the related Platform Vector Gene Therapy (PaVe-GT) program and is the NIH lead institute for BGTC, expects to contribute approximately $8 million over five years.

Private partners include Biogen Inc., Cambridge, Massachusetts; Janssen Research & Development, LLC, Raritan, New Jersey; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; Pfizer Inc., New York, New York; REGENXBIO Inc., Rockville, Maryland.; Spark Therapeutics, Philadelphia, Pennsylvania; Takeda Pharmaceutical Company Limited, Deerfield, Illinois; Taysha Gene Therapies, Dallas, Texas; Thermo Fisher Scientific Inc., Waltham, Massachusetts; and Ultragenyx Pharmaceutical, Novato, California. Several non-profit partners also are involved, including the Alliance for Regenerative Medicine (ARM), Washington, D.C.; the American Society of Gene and Cell Therapy, Milwaukee, Wisconsin; CureDuchenne, Newport Beach, California; National Organization for Rare Disorders (NORD), Quincy, Massachusetts; and The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), Newark, Delaware.

In addition to NCATS, participating NIH institutes include the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Eye Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Dental and Craniofacial Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; and National Institute on Deafness and Other Communication Disorders.

The BGTC is the first AMP initiative focused on rare diseases. Other ongoing AMP projects bring together scientific talent and financial resources from academia, industry, philanthropy, and government, andfocus on improving the productivity of therapeutic development for common metabolic diseases,schizophrenia, Parkinsons disease,Alzheimers disease,type 2 diabetes and autoimmune disorders rheumatoid arthritis and systemic lupus erythematosus.

About the Foundation for the National Institutes of Health: The Foundation for the National Institutes of Health (FNIH) creates and manages alliances with public and private institutions in support of the mission of the NIH. The FNIH works with its partners to accelerate biomedical research and strategies against diseases and health concerns in the United States and across the globe. Established by Congress in 1990, the FNIH is a not-for-profit 501(c)(3) charitable organization. For additional information about the FNIH, please visithttps://fnih.org.

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visithttps://ncats.nih.gov.

About the Food and Drug Administration (FDA): The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

###

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NIH, FDA and 15 private organizations join forces to increase effective gene therapies for rare diseases - National Institutes of Health

For Immediate Release: October 27, 2021

The U.S. Food and Drug Administration, the National Institutes of Health, 10 pharmaceutical companies and five non-profit organizations have partnered to accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease. While there are approximately 7,000 rare diseases, only two heritable diseases currently have FDA-approved gene therapies. The newly launched Bespoke Gene Therapy Consortium (BGTC), part of the NIH Accelerating Medicines Partnership (AMP) program and project-managed by the Foundation for the National Institutes of Health (FNIH), aims to optimize and streamline the gene therapy development process to help fill the unmet medical needs of people with rare diseases.

By leveraging on experience with a platform technology and by standardizing processes, gene therapy product development can be accelerated to allow more timely access to promising new therapies for patients who need them most, said Peter Marks, M.D., Ph.D., Director of the Food and Drug Administration (FDA)s Center for Biologics Evaluation and Research. FDA is committed to developing a regulatory paradigm that can advance gene therapies to meet the needs of patients with rare diseases.

Most rare diseases are caused by a defect in a single gene that could potentially be targeted with a customized or bespoke therapy that corrects or replaces the defective gene, said NIH Director Francis S. Collins, M.D., Ph.D. There are now significant opportunities to improve the complex development process for gene therapies that would accelerate scientific progress and, most importantly, provide benefit to patients by increasing the number of effective gene therapies.

A single rare disease affects small numbers of people, but rare diseases collectively affect millions. Most rare inherited diseases stem from a specific gene mutation that is already known, making gene therapy a promising therapeutic approach. However, gene therapy development for rare diseases is highly complex, time consuming and expensive. Moreover, the development process is stymied by limited access to tools and technologies, lack of standards across the field, and a one-disease-at-a-time approach to therapeutic development. A standardized therapeutic development model that includes a common gene delivery technology (a vector) could allow for a more efficient approach to specific gene therapies, saving time and cost.

Rare diseases affect 25 to 30 million Americans, but because any given rare disorder affects so few patients, companies often are reluctant or unable to invest the years of research and millions of dollars necessary to develop, test and bring individualized gene therapy treatments for a single disease to market, said Joni L. Rutter, Ph.D., acting director of NIHs National Center for Advancing Translational Sciences (NCATS). The BGTC aims to make it easier, faster and less expensive to pursue bespoke gene therapies in order to incentivize more companies to invest in this space and bring treatments to patients.

A primary aim of BGTC is to improve understanding of the basic biology of a common gene delivery vector known as the adeno-associated virus (AAV). BGTC researchers will examine the biological and mechanistic steps involved in AAV vector production, vector delivery of genes into human cells and how therapeutic genes are activated in target cells. These results will provide important information for improving the efficiency of vector manufacturing and enhancing the overall therapeutic benefit of AAV gene therapy.

To improve and accelerate gene and vector manufacturing and production processes, the BGTC program will develop a standard set of analytic tests to apply to the manufacture of viral vectors made by consortium researchers. Such tests could be broadly applicable to different manufacturing methods and make the process of developing gene therapies for very rare conditions much more efficient.

A clinical component of BGTC-funded research will support between four and six clinical trials, each focused on a different rare disease. These diseases are expected to be rare, single-gene diseases with no gene therapies or commercial programs in development and that already have substantial groundwork in place to rapidly initiate preclinical and clinical studies. The trials will employ different types of AAV vectors that have been used before in clinical trials. For these trials, the BGTC will aim to shorten the path from studies in animal models of disease to human clinical trials.

The BGTC also will explore methods to streamline regulatory requirements and processes for the FDA approval of safe and effective gene therapies, including developing standardized approaches to preclinical testing (e.g., toxicology studies).

NIH and private partners will contribute approximately $76 million over five years to support BGTC-funded projects. This includes about $39.5 million from the participating NIH institutes and centers, pending availability of funds. NCATS, which developed the related Platform Vector Gene Therapy (PaVe-GT) program and is the NIH lead institute for BGTC, expects to contribute approximately $8 million over five years.

Private partners include Biogen Inc., Cambridge, Massachusetts; Janssen Research & Development, LLC, Raritan, New Jersey; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; Pfizer Inc., New York, New York; REGENXBIO Inc., Rockville, Maryland.; Spark Therapeutics, Philadelphia, Pennsylvania; Takeda Pharmaceutical Company Limited, Deerfield, Illinois; Taysha Gene Therapies, Dallas, Texas; Thermo Fisher Scientific Inc., Waltham, Massachusetts; and Ultragenyx Pharmaceutical, Novato, California. Several non-profit partners also are involved, including the Alliance for Regenerative Medicine (ARM), Washington, D.C.; the American Society of Gene and Cell Therapy, Milwaukee, Wisconsin; CureDuchenne, Newport Beach, California; National Organization for Rare Disorders (NORD), Quincy, Massachusetts; and The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), Newark, Delaware.

In addition to NCATS, participating NIH institutes include the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Eye Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Dental and Craniofacial Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; and National Institute on Deafness and Other Communication Disorders.

The BGTC is the first AMP initiative focused on rare diseases. Other ongoing AMP projects bring together scientific talent and financial resources from academia, industry, philanthropy, and government, and focus on improving the productivity of therapeutic development for common metabolic diseases, schizophrenia, Parkinsons disease, Alzheimers disease, type 2 diabetes and autoimmune disorders rheumatoid arthritis and systemic lupus erythematosus.

About the Foundation for the National Institutes of Health: The Foundation for the National Institutes of Health (FNIH) creates and manages alliances with public and private institutions in support of the mission of the NIH. The FNIH works with its partners to accelerate biomedical research and strategies against diseases and health concerns in the United States and across the globe. Established by Congress in 1990, the FNIH is a not-for-profit 501(c)(3) charitable organization. For additional information about the FNIH, please visit https://fnih.org.

About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.

About the Food and Drug Administration (FDA): The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA, NIH, and 15 private organizations join forces to increase effective gene therapies for rare diseases - FDA.gov

For many students, attending college marks the first time away from home, the first time managing a budget, even the first time doing laundry. New spaces, new classes, new friends, new routines. This year, its not just new for the freshmen. For many, late August will mark their first return to campus since March 2019. In anticipation of Move-In, Penn Today asked six undergraduate students in the Philadelphia area this summer to divulge their favorite spots.

Ariana Jimnez found her niche on an exploratory walk, while Steven Chen and Quinn Gruber found theirs through special interests, and Lucas Monroe gravitates to athletic history. Francisco Barrera chose a study spaceand where he goes to decompress. Dorms, libraries, and outside spaces are all on the list. Morgan Bacon is most looking forward to Hey Day to kick off this semester. Its nerve-wracking to be declared a senior, but also very exciting. Ive enjoyed my time at Penn so much, she says. I can't wait to reconnect with my friends and just hang out on the grass.

Steven Chens first engagement with Penn was through the Netter Center for Community Partnerships, and as aPenn Program for Public Service intern, the biology major from Warminster, Pennsylvania now works through Netter Centers OurSpace to host weekly meetings with a group of West Philadelphia and Penn students at the LGBT Center, one of his favorite campus spots. Its a very accepting space, Chen says, a place for them to have fun and express themselves.

The sophomore is currently collaborating with the LGBT Center and the Netter Center to develop aqueer sexual health education program that utilizes peer-assisted learning. A pre-med student, Chen is interested in providing health care access to queer people and people of color. You have to be healthy to pursue your other dreams, he says. Health is the foundation.

I like a good puzzle or challenge, says Ariana Jimnez, who plans to investigate white-collar crime as an FBI agent. This requires business-industry experience, so the sophomore from Plainfield, Illinois is enrolled in the Wharton School, concentrating on finance and social impact.

She passed the benches in the engineering quad on a walk one day, and which has since become a favorite place to chill and listen to music, Jimnez says. Currently Im bingeing Taylor Swift before her new album comes out.

Jimnez is looking forward to having the opportunity to engage with people face-to-face this fall, she says. Shes also looking forward to living in New College House West. You already know Im going to be exploring that as soon as I get in there, she says. While on routine walks, Im always trying to look in to see if it looks cool, Jimnez says. And it does look cool.

Francisco Barrera of Miami, Florida is really interested in the energy problem. Barrera wants to part of the solution, so he applied to Penns Vagelos Integrated Program in Energy Research, where the senior is studying engineering and physics. Barrera spent his summer doing research with Deep Jariwala of the Device Research and Engineering Laboratory, looking into new materials and new configurations for maximizing light absorbance and efficiency for the next generation of solar cells, he says.

Barreras favorite place to study is the Fisher Fine Arts Library. Im always surrounded by STEM. The Fine Arts Library is a little bit of an escape from that, he says. I was always totally inspired by how beautiful the inside was. Its so quiet compared to other study spaces.

When not working, Barrera heads to the beach volleyball court, a great stress reliever, he says, especially during freshman year when the Miami student was adjusting to college life. The sandy court makes it more fun and athletic, Barrera says, Im more willing to throw myself down to dive for a ball.

A double major in English and Italian from Cortlandt Manor, New York, Quinn Gruber loves the Student Projects Space at the Kelly Writers House. The space is special for me because its the home of the Zine Library, a student-run collection of zines (small, self-published books/pamphlets/print objects) that Ive helped curate for three years now, with Alyson del Pino (C21) and now Victoria Garcia (C23), says Gruber, currently a senior. I love hanging out on the green beanbag with a hot cup of tea and reading the amazing zines that we have in the library, and appreciate the space as a great resource for students who make art,since we have supplies,books, and printing available for everybody.

Gruber also plays violin in a Penn Chamber Quartet, an important reprieve from the pressures of work and school, they say. Gruber enjoys visiting the Eugene Ormandy Music & Media Center to borrow whatever piece Im working on, whether for Chamber or myself, and to discover new music by just wandering through the stacks, they say.

I was always really passionate about nutrition, and more specifically childhood nutrition, says Morgan Bacon. Growing up in Philadelphia, Bacon was acutely aware of food deserts, and began working with the Food Trust. Along with social determinants, she realized how big of a role nutrition played in heath, and applied to Penn Nursing.

The Annenberg Center is one of Bacons favorite places, because the senior attended a performing arts camp here as a child, which piqued my interest in college, she says. It all seemed like a glamorous life.

Once on campus, Bacon spent two years living at Lauder College House. I just loved it so much, she says. The courtyard area was a space where the house could come together.

Im on the basketball team, so thats an easy choice for me, says Lucas Monroe of Abington, Pennsylvania, of why he chose the Palestra as one of his favorite campus spots. But Im also a huge basketball nerd and the Palestra is the cathedral. Its Mecca. More games have been played there than in any other college arena, and thats why its so historic. I like to sit at the top, he says. Ill do homework up there; Ill read up there.

Monroe, a junior majoring in political science with a minor in Africana Studies, also likes to work on the hill outside of Van Pelt-Dietrich Library. Its a peaceful spot, he says, but also one thats good for people watching. You have the library to the left of you, College Hall diagonal. The Franklin statue and the Button are all right there; theres a lot of cool things you can look at.

Homepage image: Clockwise from top left: Morgan Bacon, Ariana Jimnez, Francisco Barrera,Quinn Gruber, Lucas Monroe, and Stephen Chen introduce their favorite places at Penn.

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People and places at Penn | Penn Today - Penn Today - Penn Today

The Department of Health and Human Services (HHS) has funneled at least $2.7 million into a University of Pittsburgh (Pitt) project that utilizes a tissue bank with organs from aborted fetuses, according to a release from Judicial Watch Tuesday.

The conservative nonprofit obtained hundreds of pages of public records requests, which detail Pitt's interest in harvesting fetal organs for a project known as the GenitoUrinary Development Molecular Anatomy Project, or GUDMAP. More money was requested by the university but it's unclear exactly how much it received.

Pitt's application specified that it sought to "develop a pipeline to the acquisition, quality control and distribution of human genitourinary [urinary and genital organs and functions] samples obtained throughout development (6-42 weeks gestation)." Forty-two weeks represents more than 10 months of pregnancy.

In 2015, Pitt told HHS that it has been "collecting fetal tissue for over 10 years includ[ing] liver, heart, gonads, legs, brain, genitourinary tissues including kidneys, ureters and bladders."

It also revealed that the university sought a large number of minority fetuses, according to Judicial Watch something Center for Medical Progress founder David Daleiden described as "racist."

TESTIMONY FROM PLANNED PARENTHOOD, TISSUE PROCURER SHEDS LIGHT ON BABIES BORN ALIVE, WITH BEATING HEARTS

The university told Fox News that the higher number of minorities resulted from an emphasis on those populations most impacted by kidney disease. "Projects funded by the National Institutes of Health must ensure appropriate inclusion of women and minorities," said David Seldin, assistant vice chancellor for news.

"They should also ensure distribution of the study reflects the population needed to accomplish the scientific goals of the study. Asked another way: Does the makeup of the study reflect the populations affected by the illness in question? In the case of the GUDMAP Tissue Hub, one of the goals is to support researchers looking for treatments and cures for kidney disease."

In a PureFlix interview last year, former university employee Lori Kelly discussed a federally funded project with researchers seeking to collect bladders and kidneys from babies as late as 24 weeks into pregnancy. Kelly said that as project manager, she worked to develop "a pull-down menu of baby body parts for researchers to choose from to submit to the tissue bank, so that we could send the body parts to them."

BLACK PRO-LIFE LEADERS PAN PLANNED PARENTHOOD'S SANGER DISAVOWAL: LIKE CHANGING THE NAME OF AUSCHWITZ

"And these researchers were all across the United States," she said,"from Florida to California." When asked, the University of Pittsburgh did not respond to Kelly's allegations earlier this year.

Both the university and its medical center have denied any wrongdoing.

Tuesday's revelation adds mounting scrutiny to a school that has already received attention for its use of fetal tissue.

"The University of Pittsburgh complies with rigorous regulatory and ethical oversight of fetal tissue research," Paul Supowitz, the university's vice chancellor, previously told lawmakers."The researchers in this matter followed all applicable federal and state guidelines and regulations (with Pennsylvania having one of the most restrictive set of requirements in the nation), as well as strict protocols approved by the University. The Universitys Institutional Review Board approved the acquisition of stem cells."

The National Institutes of Health (NIH) has also maintained that it complies with federal law. It previously told Fox News: "NIH is committed to ensuring that research involving human fetal tissue is conducted responsibly and meets the highest ethical standards."

ON THE 48TH ANNIVERSARY OF ROE V. WADE, QUESTIONS REMAIN IN PLANNED PARENTHOOD CONTROVERSIES

Earlier this year, Pennsylvania's state legislature held a hearing in which members discussed an experiment involving grafting fetal scalps, containing "full-thickness human skin," onto rodents.

That particular project utilized tissue from the university's human tissue bank. It was also supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), which is led by top coronavirus adviser Dr. Anthony Fauci. While it's unclear exactly how much federal money was spent on that project, it was funded through two large grants one $1,498,642 and one $430,270.

David Daleiden, the anti-abortion journalist who testified at May's hearing, said on Tuesday: "The NIH grant application for just one of Pitts numerous experiments with aborted infants reads like an episode of American Horror Story People are outraged by such disregard for the lives of the vulnerable. Law enforcement and public officials should act immediately to bring the next Kermit Gosnell to justice under the law."

The documents uncovered by Judicial Watch also show Pitt discussing its effort to minimize warm ischemic time, or the amount of time an organ maintains its body temperature after blood flow has been severed. It's unclear how these procedures take place, but Daleiden has raised concerns about the university's stated use of labor induction abortions.

ELIZABETH WARREN: ABORTION IS ABOUT THE FUNCTIONING OF OUR DEMOCRACY

"If the fetus heartbeat and blood circulation continue in a labor induction abortion for harvesting organs, it means the fetus is being delivered while still alive and the cause of death is the removal of the organs," reads a press release from his Center for Medical Progress. Typically, abortion procedures rely on digoxin to kill a fetus. However, both that and dismemberment tactics can ruin viable tissue intended for donations.

In a statement to Fox News, Seldin said clarified the researchers have "no part in any decisions as to timing, method, or procedures used to terminate the pregnancy."

Ischemia time, he said "refers to the time after the tissue collection procedure and before cooling for storage and transport. It does not have an impact on how the procedure is performed, which is always at the discretion of the attending physician and determined with the patients health as the top priority."

Seldin added that all tissue was obtained in compliance with the Pennsylvania Abortion Control Act, which lays out a series of regulations for performing the procedure. It also contains a section banning infanticide, noting that: "The law of this Commonwealth shall not be construed to imply that any human being born alive in the course of or as a result of an abortion or pregnancy termination, no matter what may be that human being's chance of survival, is not a person under the Constitution and laws of this Commonwealth."

In May, the university provided Fox News with a statement defending the use of fetal tissue research.

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"Researchers at Pitt and other leading medical research institutions use fetal tissue in certain instances because it has proven to be an important method for combatting and curing some of our most devastating diseases, including ALS, Parkinsons disease, Alzheimers disease, spinal cord injury and others," read the statement.

On Wednesday, Seldin added that "[t]his grant supported research to find new therapies for diseases of the kidneys, bladder and urinary systems, which are a leading cause of organ failure. By providing a central hub for researchers across the country, this program allowed scientists across the country to access tissue necessary to tackle this growing public health concern."

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Millions in federal money flowed to tissue bank that collected fetal 'heart, gonads, legs, brain': report - Fox News

After Michael Herman received a diagnosis of high-risk multiple myeloma in 2013, he started a treatment journey that included several years of chemotherapy and the targeted drug Venclexta (venetoclax tablets), which is investigational for the disease and was designed for patients whose cancers have certain genetic abnormalities. The medicines worked well, but as is often the case with multiple myeloma, Hermans cancer eventually returned.

In July 2019, Herman qualified for a clinical trial of teclistamab, an investigational drug thats part of an emerging class of immunotherapy medicines known as bispecific antibodies. He traveled from his home in Galena, Maryland, to the University of Pennsylvania in Philadelphia to get the treatment: a weekly shot in the abdomen.

After just one dose of teclistamab, Hermans cancer load dropped 99%. His disease is no longer detectable, and the study investigators have told him he can stay on the drug as long as it continues to be effective. In terms of side effects, Herman experiences some aches and pains, but says that it doesnt affect him from getting around.

When I was diagnosed, I was told my life expectancy was four years, says Herman, 59, a retired corporate real estate manager. This drug doubled that. Its a wonderful thing.

Teclistamab is one of several bispecific antibodies being developed to treat a range of cancers. Bispecific antibodies are designed to simultaneously bind two targets a target on immune cells and another on tumor cells pulling them together to unleash an immune attack against the cancerous cells. In the case of teclistamab, the two targets are an antigen called CD3 in the immune systems T cells, and BCMA, which is an antigen thats overexpressed in multiple myeloma.

Several other bispecific antibodies are under development to treat blood cancers and a wide range of solid tumor types, including cervical, gastric, brain and liver.

The idea behind combination immune therapies, which include bispecific antibodies, is to find ways to better target the immune system from the get-go, to minimize the chance of resistance or improve the chance of getting a good response, says Dr. Deborah Wong, an oncologist at UCLA.

The first, and so far only, bispecific antibody on the market, Blincyto (blinatumomab), is approved by the Food and Drug Administration (FDA) to treat some patients with acute lymphoblastic leukemia (ALL). The drug, referred to as a bispecific T-cell engager (also referred to as BiTE), has one arm that attaches to CD3 and a second that binds to the antigen CD19 on the surface of cancerous B cells.

In a trial of patients with relapsed or resistant B-cell precursor ALL, Blincyto increased the rate of complete remissions from 20% among patients on standard-of-care chemotherapy to 42%. In a pediatric study released in March 2021, 69% of children treated with Blincyto were still alive after nearly two years, and 93% showed no sign of disease. In a phase 2 study released in May 2021, there was a 95% response rate among patients with Philadelphia chromosome-positive ALL who received Blincyto plus the targeted drug Iclusig (ponatinib), showing the potential of treating patients without the need for chemotherapy, the researchers said.

Bispecific antibodies can cause side effects, including cytokine release syndrome, a severe inflammatory response marked by high fever, body aches and other symptoms. Although Herman experienced cytokine release after his first shot of teclistamab, he has had minimal side effects since then.

Bispecific antibodies could bring immunotherapy options to patients who arent eligible for treatments like CAR T cells, which are personalized therapies that entail removing immune cells from patients and engineering them to recognize and attack their cancer. Although these T-cell therapies can be lifesaving, they present challenges that could be avoided with bispecific antibodies, says Dr. Joshua Richter, assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York.

CAR-Ts are not off-the-shelf products, so they take time for manufacturing, whereas bispecifics are off the shelf, Richter says. And even though there is a risk of side effects with bispecific antibodies, they are titratable, meaning they can be given in small doses to start and then in larger doses after the immune system is given a chance to adapt. We are concerned about giving CAR-Ts to older people because some can get quite sick (from cytokine release), Richter says. Its nice to have a more titratable alternative.

Several bispecific antibodies aimed at multiple myeloma are in clinical trials now, some of which are showing early promise. In a phase 1 dose-ranging study of an intravenous formulation of teclistamab, for example, 58% of patients on the recommended dose for phase 2 trials showed a partial response and 30% had a complete response. Although 70% of participants experienced cytokine release, none had symptoms severe enough to prompt them to pull out of the trial. Other side effects included anemia, a drop in white blood cells and fatigue. A phase 2 study of the drug in multiple myeloma is ongoing and recruiting patients.

Another trial of a BCMA-CD3-targeted bispecific antibody, elranatamab, was paused in May because of cases of peripheral neuropathy reported by some patients. The drugs developer, Pfizer, was asked to investigate the cases and report what it finds to the FDA. Patients in the trial who were benefiting from the drug were able to stay on it, but no new patients will be accepted until the investigation is complete.

There are other promising approaches to multiple myeloma in early-stage testing, Richter says, including a bispecific antibody called cevostamab, which targets CD3 and FcRH5, an antigen expressed on the surface of almost all multiple myeloma cells. Interim results from an ongoing phase 1 study that were reported in December showed an overall response rate of 53%. Responses were even seen in patients who had failed five previous treatments.

Another prospect in multiple myeloma is a bispecific antibody called GBR1342, which targets CD3 and CD38, an antigen implicated in the disease and other blood cancers. The drug, now in phase 1 testing, received orphan drug designation from the FDA in 2019, which could expedite its development path.

There are several bispecific antibodies in development to treat other blood cancers, including acute myeloid leukemia (AML). For example, a drug called flotetuzumab targets CD3 and CD123, a molecule called an interleukin-3 receptor thats prevalent on malignant cells in AML. In a trial of the drug in patients who had relapsed after other therapies, 32% of participants achieved a response, and more than half of those were able to go on to receive stem cell transplants, which put them in remission.

The flotetuzumab trial results highlighted another potential advantage of bispecific antibodies, which is that they may offer patients a bridge to other treatments that could result in more durable remissions, such as stem cell transplants. The ALL treatment Blincyto has also been shown to offer some patients a good lead-in to stem cell transplants. In a trial comparing the drug to standard-of-care chemotherapy, the overall response rate to Blincyto was 44%, and 24% of the patients receiving the drug went on to have stem cell transplants.

Oncologists at The University of Texas MD Anderson Cancer Center in Houston are now testing Blincyto in patients with newly diagnosed ALL, and there are encouraging early results. Last year, researchers reported results from a small trial in which patients with ALL started with four cycles of chemotherapy and then were placed on maintenance treatments that included Blincyto. There was a 100% response rate, and 79% of patients stayed in remission for two years.

Historically, we can cure about 40% to 50% of elderly patients with ALL, so if this response rate holds over time, it will be a tremendous improvement, essentially doubling survival rates, said Dr. Marina Konopleva, a professor and physician-scientist in the department of leukemia and stem cell transplantation at MD Anderson.

Phil Briggs, who received a diagnosis of ALL in January 2018, was treated with Blincyto in the fall of 2020, after his cancer stopped responding to standard-of-care chemotherapy. He found the drug to be far more tolerable than chemotherapy, which had caused him to lose his appetite and drop more than 50 pounds, in addition to developing peripheral nerve damage. Aside from a slight skin irritation, I felt fantastic, says Briggs, 62, who is being treated at MD Anderson.

Briggs courses of Blincyto came in a portable pump, allowing him to receive the agent on an outpatient basis without having to go to the hospital. After four months on the drug, he was able to undergo a stem cell transplant and is now in remission. I felt so much better that I was able to go straight from (Blincyto) to the stem cell trans- plant without any side effects, says Briggs, who is now planning to go back to work as an insurance salesman.

Targeting solid tumors with immunotherapy has been difficult because they lack a single target for immune cells to latch on to, and the environment that surrounds them may not be conducible for immune cells to readily attack the cancer cells. The two-pronged design of bispecific antibodies could help overcome those hurdles.

Several bispecific antibodies being developed to treat solid tumors include one treatment group that targets an immune checkpoint like PD-L1 or CTLA-4, inhibiting it so the immune system can launch an attack.

For example, a bispecific antibody called FS118, which is now being tested in a phase 1 trial in solid tumors, has one treatment group that inhibits PD-L1 and another that blocks another immune checkpoint called LAG-3. Initial results from a trial released last year showed that patients who had been treated with PD-1 or PD-L1 blockers and became resistant to them had durable stabilization of their disease on FS118.

A bispecific antibody called XmAb20717 blocks PD-1 and CTLA-4 and is being tested in patients with a number of solid tumor types. The response rate in a trial reported last November was 19% and included a complete remission in one patient with melanoma. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer.

Other bispecific antibodies in development to treat solid tumors target disease-promoting genetic mutations. One of these agents was recently approved by the FDA. Called Rybrevant (amivantamab-vmjw), it targets EGFR and MET in NSCLC with abnormalities in those genes. It is the first fully human, bispecific antibody approved in lung cancer. The approval was based on results from the phase 1 study, where the response rate to the drug was 40% in patients who had previously been treated with platinum chemotherapy, and 74% of patients saw their disease stabilize.

With so many bispecific antibodies in development across a range of cancer types, many patients could benefit from enrolling in clinical trials of these new therapies, says Wong. Clinical trials are a good option to consider, especially if youve already been on standard therapies, she says. It may be that patients who responded well to their initial therapy and then developed resistance could be good candidates for bispecific antibodies.

And because bispecifics target the immune system, they could improve the prognosis for many patients, Wong says: The beauty of immunotherapy is that the immune system has a long memory, so theres a potential for patients to have long-lasting responses to these drugs.

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The emergence of nucleic acids and that of proteins have sometimes been called the first and second evolution revolutions, as they made life as we know it possible. Some experts argue that glycosylationthe addition of glycans to other biopolymersshould be considered the third, because it allowed cells to build countless molecular forms from the same DNA blueprints. Its long been believed that only proteins and lipids receive these carbohydrate constructs, but a May 17 paper in Cellthat builds upon a 2019 bioRxiv preprint posits that RNAs can be glycosylated, too, and these sugar-coated nucleic acids seem to localize to cell membranes.

Anna-Marie Fairhurst, who studies autoimmunity at the Agency for Science, Technology and Research in Singapore, describes the study as exciting. Obviously, its the first time ever that weve seen this with RNA, she says, adding that the diversity of methods used to demonstrate the presence of glycoRNAs makes the findings especially robust.

What really intrigues her are the parts present in the 2021 Cellpaper that arent in the 2019 preprintin particular, that glycoRNAs appear to predominantly end up on the cells outer membrane. There, they can attach to two kinds of sialic acid-binding immunoglobulin-type lectins (Siglecs)a family of immune receptors implicated in several diseases, including systemic lupus erythematosus (SLE). All of this suggests glycoRNAs may play a role in immune signaling. Its a really exciting era of science, Fairhurst says.

Ryan Flynn, the first author on the new paper and an RNA biologist at Harvard University and Boston Childrens Hospital, says he made the startling discovery of glycoRNAs while working in chemical biologist Carolyn Bertozzis lab at Stanford University. Bertozzi says she was skeptical at first but came around after thinking about how her own assumptions might be shaping her views. We bring to every experiment all this unconscious bias, she explains, and once she re-examined her own, she found no reason to think glycoRNAs shouldnt exist. These are ancient molecules, she says. Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

These are ancient molecules . . . Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

Carolyn Bertozzi, Stanford University

As it happens, Flynn did set out to overturn glycosylation dogma when he joined Bertozzis lab as a postdoc in 2017although it didnt happen the way he expected. At first, he explains, he had his eye on a quirky cytosolic protein glycosylation pathway because hed noticed that one of its key enzymes has an RNA-binding domain. If theres a glycosylation enzyme with the potential to bind RNA, and its functioning in the cytosol where RNAs tend to be, he reasoned, it could be sticking sugars to RNAs, too.

To search for the existence of these structures, it was really important that I had access to things that were not dependent on high temperatures, and not dependent on metals that might otherwise degrade the RNA, he says, and thats exactly what Bertozzis lab had to offer. Shes a pioneer in the field of bioorthogonal chemistry, which aims to develop chemical methods for tracking biomolecules in their native environments. Her lab was brimming with reagents that label specific kinds of glycans without harming other molecules or setting off side-reactions.

Flynn set to work adding these glycan-labeling compounds to HeLa cells and then isolating RNA from them to see if any glycan signal remained after hed removed all proteins and lipids. He says he thought he might see a signal when he labeled the kind of glycans used in that cytosolic glycosylation pathway.

However, months of experiments failed to support that hypothesis.

Instead, something strange kept happening with what was supposed to be a negative control: cells treated with ManNAz, an azide-labeled precursor for sialoglycans, a group of glycans known for their role as modifiers of secretory and cell surface proteins and lipids. Once the cells were given the chance to incorporate ManNAz, they were lysed with TRIzol, which breaks apart cellular components without damaging RNAs, and any surviving proteins were chopped up with proteases. The idea was that thered be no azide signal at the end, as sialoglycans are attached to proteins and lipids in the endoplasmic reticulum and Golgi, where RNAs have no business being. I was like, theres no way that a reagent that labels sialoglycans is going to end up labeling an RNA, even a glycoRNA, Bertozzi says, but those experiments consistently gave Flynn positive signals.

So, the team dug further. Not only did the glycoRNAs the team found contain this specific subgroup of glycans, they appeared to largely consist of YRNAs, a family of small, highly conserved noncoding RNAs whose cellular functions remain unclear, although previous studies have suggested they may play a role in oncogenesis and autoimmunity. The specificity of both the glycans and the type of RNAs involved strongly point to their being attached to one another with an enzyme, says Bertozzi.

Furthermore, once the researchers started looking for them, they found these glycoRNAs in numerous established cell lines, including cancer-derived ones such as HeLa and T-ALL 4118 cells, as well as stem cellderived CHO and H9 cells. They were even able to detect glycoRNAs in liver and spleen cells extracted from live mice that received intraperitoneal injections of ManNAz, suggesting that glycoRNAs are everywhere.

By 2019, the team members felt they had enough supportive data to submit their findings, so they put the preprint version up on bioRxiv. It made a splash in the scientific community, but without peer review, some remained skeptical. Now, after even more experiments and a rigorous review process, the team says its data have become even more compelling.

They clearly have isolated a covalent RNA-glycan conjugate, says Laura Kiessling, a chemical biology researcher who studies carbohydrates at MIT and was not involved in the study. However, big questions remain, including what these glycoRNAs do and how they form. For instance, its unclear exactly how the RNAs and glycans are physically connected to one another, she notes, and without that information, shes not quite convinced that the binding happens enzymatically.

Flynn and Bertozzi suggest that the RNAs are glycosylated much in the same way proteins are, and that it even requires some of the same proteins. As noted in the original preprint, when they inhibited key enzymes involved in glycosylation, glycoRNAs disappeared in a dose-dependent manner. Similarly, cell lines engineered to have errors in protein glycosylation produced very little glycoRNA. But for RNAs to be glycosylated by the same pathway as proteins would be weird, Kiessling says, noting that multiple glycosylation steps only proceed after a check for proper protein folding. Its hard for me to imagine exactly how that would occur with RNA.

The researchers were even able to detect glycoRNAs in liver and spleen cells extracted from live mice, suggesting that glycoRNAs are everywhere.

Fairhurst says she also wants to know more about the synthesis pathway. She has lots of other questions, too, which she says is a good sign. A really good, exciting paper leaves a lot more questions than it does answers, she notes.

While the 2019 preprint raised many of these questions, some are unique to the new data presented in the Cell version. Perhaps the biggest addition to the work was the discovery of where these glycoRNAs spend their timestuck on the outsides of cells, explains Flynn. The team demonstrated this by briefly exposing some ManNAz-labeled HeLa cells toan enzyme that can cleave sialic acid glycans from the cell surface. If the glycoRNAs were on the outside, they would be cut off, and the total amount of glycoRNAs remaining would drop. And thats exactly what they found: the glycoRNA signal started to decrease after as little as 20 minutes of incubation with the sialidase and was reduced by more than 50 percent after an hour, which the team suggests means that more than half of a cells glycoRNAs are stuck on its outer membrane.

The researchers further probed the hypothesis of extracellular localization by labeling living cells with an antibody that binds to double-stranded RNA. About one-fifth of a culture of HeLa cells were positive for antibody staining, and the label was sensitive to RNase treatment, further supporting the idea that glycoRNAs are indeed present on the outer cell membrane. That opens up a lot of ideas, and a lot of possibilities, functionally and mechanistically, for what they could be doing, says Flynn.

One of those possibilities is that glycoRNAs are involved in cell-to-cell signaling, especially in an immune context, as thats a known function of membrane glycolipids and glycoproteins. Bertozzi had already been investigating the ligands of Siglecs, a group of sugar-binding receptors that modulate immune reactions, so the team decided to see if any of them bound to glycoRNAs. They first treated HeLa cells with different Siglecs to show that the receptors bound normally, then treated the cells with RNase. Lo and behold, the binding of Siglec-11 and Siglec-14 dropped precipitously, suggesting that their ligands were cleaved from the surface by the RNA-cutting enzyme.

Bertozzi says the experiment indicated glycoRNAs are ligands for Siglec-11 and Siglec-14, and if so, theyd be the first identified for Siglec-11.

As a receptor family, [Siglecs have] kind of been ignored, notes Fairhurst, so the fact that these glycoRNAs can interact with them is very exciting, she says. My immediate desire is to see whether they are associated with diseases, particularly in SLE, she adds.

Lan Lin, an RNA biologist at the University of Pennsylvania and the Childrens Hospital of Philadelphia, says she found the 2019 preprint so interesting that she applied for and received a pilot grant from the Frontiers in Congenital Disorders of Glycosylation (CDG) Consortium to study the roles glycoRNAs may play in CDG, a group of rare congenital conditions arising from mutations in protein glycosylation pathways. Because RNA glycosylation may be related to protein glycosylation, she tells The Scientist, it was only rational or reasonable for [my colleagues and I] to hypothesize that . . . some of these patients might have differences in the glycoRNA in their system, and therefore, CDG conditions could be used to examine the potential functions of glycoRNAs.

So far, she says, her team hasnt detected any consistent differences in glycoRNAs between the cells of healthy controls and CDG patients. She says that may be because differences are more qualitative than quantitative, such as alterations to the sugars themselves or the subset of RNAs that are glycosylated. Alternatively, she notes, the new data in the 2021 Cell paper may provide an explanation: the membrane localization of glycoRNAs wasnt in the preprint, so maybe we are looking in the wrong place, she muses.

Its also possible that new methods are needed to detect glycoRNA differences between cells. She points out that a major limitation of the study is that the ManNAz labeling method cant readily be applied to preserved human tissue samples or blood samples.

Fairhurst says shed like to see more work in primary cell cultures rather than immortalized ones, especially leukocyte subtypes, where one might expect pronounced differences if the RNAs have a role in immunity. For example, she says shed like to see whether, in people with conditions like SLE, different cell types have fewer or more glycoRNAs, though obviously, those experiments are really challenging.

Seeing these big milestones is amazing

Anna-Marie Fairhurst, Agency for Science, Technology and Research in Singapore

Still, she says, seeing these big milestones is amazing.

Kiessling says she thinks glycoRNAs could be really important in the field of glycobiology. Her lab focuses on how carbohydrate-binding proteins can read glycans on the surfaces of cells, she explains, so these glycoRNAs could be a new kind of information to read. Lin points out that the findings are especially impactful for RNA researchers, as they suggest a whole new kind of post-transcriptional modification in need of investigation. Because glycoRNA sits at the intersection of glycobiology, immunology, and RNA biology, says Bertozzi, Ryans discovery has brought together these disparate worlds.

Flynn and Bertozzi say theyre hoping to start answering some of the many questions that remain, including how the glycans attach to RNAs and how and where that happens. The most exciting part, they say, will be the investigations into what glycoRNAs do.

R. Flynn et al., Small RNAs are modified with N-glycans and displayed on the surface of living cells,Cell, doi:10.1016/j.cell.2021.04.023, 2021.

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