Category Archives: Cell Medicine

A monoclonal antibody treatment called leronlimab could reduce long COVID symptoms in some patients, according to a recent pilot study published in the journal Clinical Infectious Disease.

The studys results suggest that leronlimab can alleviate long COVID symptoms by boosting the immune system in individuals who previously had a suppressed immune system.

Scientists have considered persistent inflammation as one of the causes underlying long COVID. In contrast, the studys findings suggest that the downregulation of the immune system could be responsible for long COVID in some individuals.

A majority of individuals with COVID-19 recover fully within the initial 3-4 weeks after contracting the illness. However, around 10-30% of individuals experience lingering symptoms weeks and months after the acute phase of the illness. These symptoms have been collectively described as long COVID or post-acute COVID-19 syndrome.

Since the symptoms of long COVID vary from person to person, the mechanisms underlying long COVID are not well understood. This has also hindered the development of treatments targeting the factors responsible for causing long COVID.

Severe illness during the acute phase of a SARS-CoV-2 infection is characterized by excessive inflammation and a dysregulated immune response. Scientists have hypothesized that these atypical immune responses during the acute infection phase could lead to persistent inflammation. This chronic inflammation could be potentially responsible for long COVID symptoms.

Indeed, studies have reported that individuals with long COVID show elevated levels of inflammatory cytokines, which are a class of proteins involved in mediating the bodys immune response.

Thus, scientists have been turning to treatments that normalize the immune system to help alleviate symptoms of long COVID. One such candidate is the monoclonal antibody leronlimab which blocks the cytokine receptor CCR5.

The CCR5 receptor is expressed by immune cells and is involved in mediating an immune response against an infection. Previous studies have shown that leronlimab can reduce the levels of inflammatory cytokines in individuals hospitalized with severe COVID-19.

Hence, the studys authors decided to assess the ability of leronlimab in reducing long COVID symptoms.

The present study involved 55 individuals with long COVID who received a weekly injection of either leronlimab or saline placebo over an 8-week period.

To evaluate the effectiveness of leronlimab, the researchers tracked changes in 24 symptoms commonly associated with long COVID over the duration of the study.

They found that a higher percentage of individuals in the leronlimab-treated group showed improvements in several long COVID symptoms than in the placebo group.

However, not all individuals receiving leronlimab showed an improvement in their symptoms.

The researchers then examined the impact of leronlimab on CCR5 expression in long COVID.

Individuals treated with leronlimab showed an increase in the percentage of immune cells expressing CCR5 after 8 weeks. The control group did not show an increase in their CCR5 expression.

In addition, the researchers found differences in CCR5 expression among individuals within the leronlimab-treated group. Individuals who responded to leronlimab showed lower levels of CCR5 expression at the beginning of the study than those who did not respond to the treatment.

Significantly, only individuals in the leronlimab-treated group who responded to the treatment showed an increase in CCR5 expression during the 8-week period. Such an increase in CCR5 expression was absent in non-responders.

The studys co-author, Dr. Otto Yang, a professor of medicine at the University of California in Los Angeles, explains:

Patients who improved were those who started with low CCR5 on their T cells, suggesting their immune system was less active than normal, and levels of CCR5 actually increased in people who improved.

Dr. Yang indicates that this could change approaches to long COVID treatments.

This leads to the new hypothesis that long COVID in some persons is related to the immune system being suppressed and not hyperactive and that while blocking its activity, the antibody can stabilize CCR5 expression on the cell surface leading to upregulation of other immune receptors or functions, he says.

The researchers also found that treatment with leronlimab increased the number of specific immune cell populations, such as T cells. This further suggests that blocking CCR5 with leronlimab boosted the immune system in some individuals with long COVID.

Dr. Rajeev Mehlotra, a research associate at Case Western Reserve University, who was not involved in the study, told Medical News Today that the findings add another perspective to efforts to understand long COVID.

As the studies targeting CCR5 for COVID-19 treatment are performed, and such treatments start becoming increasingly available, this study adds another view to the mechanism associated with leronlimab treatment, Dr. Mehlotra said.

Considering this unexpected mechanism together with existing knowledge may lead to a more comprehensive understanding of the pathogenesis and treatment outcomes in COVID-19 patients, he added.

Previous studies have shown that individuals who are genetically predisposed to express lower levels of CCR5 are at an increased risk of severe COVID-19. Similar genetic differences that influence CCR5 expression could influence whether individuals with long COVID respond to leronlimab treatment.

Dr. Saurabh Mehandru, a professor of gastroenterology at the Icahn School of Medicine at Mount Sinai, told MNT that the studys findings could help reveal some of the yet-unknown mechanisms behind long COVID.

It is encouraging to note that there are interesting cellular and receptor expression differences between treatment responders and non-responders. This could suggest an underlying biological mechanism that could be further explored in pre-clinical or clinical studies on patients with long COVID, he said.

Original post:
Are we treating long COVID wrong? Immune-boosting treatment takes new approach - Medical News Today

In Vivo Gene Delivery Platform Will Dramatically Expand the Benefit and Reach of Genetic Medicines

Founded and Led by Leading Experts in Immunology, Oncology, and Cell and Gene Therapy

Strategic Collaborations with Leading Industry Partners Enable and Accelerate Platform Capabilities

BOSTON, April 28, 2022--(BUSINESS WIRE)--Kelonia Therapeutics, a biotech company revolutionizing in vivo gene delivery, launched today with a $50 million Series A financing to usher in a new era of genetic medicines for a wide range of diseases. Kelonias platform overcomes the central challenge that has prevented the full realization of gene therapy for patients. Despite life-changing responses, existing gene therapies are highly complex, costly, and limited by complicated treatment paradigms, tractable therapeutic applications, and dose-limiting toxicities. By enabling precisely targeted, highly efficient, manufacturable "off-the-shelf" in vivo gene delivery, Kelonias technology has the potential to dramatically expand the impact and reach of genetic medicines to every patient in need.

Kelonia is backed by a strong syndicate of investors with a track record of successfully launching and building disruptive biotech companies. Alta Partners, Horizons Ventures, Venrock and other investors participated in the Series A round. The company will use the funding to redefine whats possible for genetic medicines starting with an "off-the-shelf" chimeric antigen receptor (CAR) to treat hematologic cancer that may enable the unrivalled clinical benefit of CAR T without the typical toxicities and with the ease of access of conventional medicines. Additionally, the company will advance other programs for oncology and non-oncology indications, and further expand its gene delivery platform and capabilities.

"The cell and gene therapy field has been searching for solutions to durable in vivo genetic modifications regardless of whether applying gene editing, RNA expression or viral-mediated gene integration," said Kevin Friedman, Ph.D., President and Chief Scientific Officer of Kelonia. "At Kelonia, we believe we have found an in vivo gene delivery solution that is safe, effective, and manufacturable for broad therapeutic application. With our Series A funding and key strategic collaborations, we will advance our lead product candidate toward clinical studies and further optimize our technology to explore treating diseases never thought possible with genetic medicines."

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Based on discoveries made in the lab of Massachusetts Institute of Technologys Michael Birnbaum, Ph.D., and leveraging pioneering research from leading scientists at the French National Centre for Scientific Research (CNRS), Kelonias in vivo gene delivery technology enables a few potent lentiviral vector-like particles armed with an adjustable targeting system to precisely, efficiently, and safely deliver payloads exactly where needed to treat a broad range of diseases. The companys early applications combine oncology-targeted therapeutics, such as CAR and T cell receptor molecules, with Kelonias precision in vivo targeting technology. When used in concert, this combination enables potent and precise tumor targeting with limited "off-tumor" toxicity, which would otherwise be a concern. Administered directly in vivo as an "off-the-shelf" medicine, Kelonias transformational therapies in development for solid and hematologic tumors have the potential to democratize patient access to genetic medicines. Beyond oncology, the company will advance its technology to unlock delivery to previously hard-to-reach tissues, such as neurological, muscular or renal, to deliver different types of genetic cargo with the goal of radically transforming the treatment of diseases in these areas.

"It turns out, a relatively simple and elegant idea to de-target and redirect lentivirus-like particles based on recently published research from my lab can potentially provide a solution to in vivo gene delivery," said Dr. Birnbaum, Ph.D., Co-Founder of Kelonia. "Im incredibly excited about the potential of Kelonias platform and team to vastly expand the utility of gene therapies to treat oncology, autoimmune disease, rare monogenic or other diseases currently intractable to gene therapies."

"Kelonia is combining the two crucial elements required to develop truly novel medicines: breakthrough biology and an exceptional team," said Bryan Roberts, Partner at Venrock. "Michael Birnbaums industrially robust platform affords a targeting specificity log orders better than anything else out there and the team has a stellar track record for translating groundbreaking scientific gene therapy discoveries into viable products that are transformative for patients."

Strategic Collaborations

In addition to the completion of its Series A, Kelonia has established strategic collaborations with Adimab and ElevateBio. With both collaborations already successfully underway, each of these outstanding partners brings differentiating capabilities that enable and accelerate the companys vision to bring breakthrough genetic medicines to patients.

Adimab is the leading provider of therapeutic antibody discovery and engineering technologies. Kelonia will leverage Adimabs expertise and proprietary technologies, across a range of applications, to access tissue-specific antibodies that enable unlocking precise in vivo gene delivery to different tissues as well as antibodies that can be leveraged within the therapeutic genetic cargo.

ElevateBio is a technology-driven company focused on powering transformative cell and gene therapies with multiple next-generation technology platforms and a fully integrated R&D and manufacturing facility. Through an expanding partnership, Kelonia will utilize ElevateBios lentiviral vector platform, process and analytical development expertise, and cGMP manufacturing capabilities to develop and advance novel manufacturing processes for Kelonia and manufacture of Kelonias products.

Leadership and Founding Team

Kelonia brings together industry leaders in cell and gene therapy responsible for the discovery and development of multiple clinical and commercial products including ABECMA, the first FDA-approved anti-BCMA CAR T cell therapy product for relapsed or refractory multiple myeloma. The companys leadership team includes Kevin Friedman, Ph.D., President and Chief Scientific Officer, Thomas Galbo, Ph.D., Chief Business Officer, and Molly Perkins, Ph.D., Vice President of Research.

Kelonias scientific founders include Michael Birnbaum, Ph.D., Associate Professor of Biological Engineering, Massachusetts Institute of Technology, and Michael Fischbach, Ph.D., Associate Professor of Bioengineering and of Medicine, Stanford University, both world-leading experts in the fields of microbiology, immunology, oncology, and cell and gene engineering.

The companys board of directors comprises Michael Birnbaum, Michael Fischbach, Kevin Friedman, Bryan Roberts and Bob More, Managing Director at Alta.

About Kelonia TherapeuticsKelonia is pioneering a new wave of genetic medicines using its next generation gene delivery platform. The companys simple and elegant cutting-edge in vivo gene delivery technology uses a few potent lentiviral vector-like particles to precisely and efficiently deliver in vivo genetic cargo to the desired target tissue, and only that tissue, every time. With an initial focus on developing transformational therapies for solid tumors and hematologic cancers, Kelonia is building a pipeline of genetic medicines for a wide range of diseases, with the bold goal of bringing genetic medicines to every patient in need. Learn more about Kelonia at http://www.keloniatx.com and follow us on LinkedIn and Twitter.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220428005083/en/

Contacts

Michele RozenScient PRmrozen@scientpr.com

The rest is here:
Kelonia Therapeutics Launches with $50 Million Series A Financing to Pioneer Precision Targeted Genetic Medicines - Yahoo Finance

Hagop M. Kantarjian, MD, discusses how the treatment landscape of acute lymphocytic leukemia compares to what it used to be.

Hagop M. Kantarjian, MD, professor, department of Leukemia, division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses how the treatment landscape of acute lymphocytic leukemia (ALL) compares to what it used to be.

The ongoing paradigm shift in the treatment of ALL can be credited to the introduction of the BCR-ABL tyrosine kinase inhibitors as well as new antibodies targeting CD19, CD20 and CD22. Agents like ponatinib (Iclusig), blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa) have also yielded positive results in regard to survival and rates of remission within this patient population.

Kantarjian hopes that by combining these agents with one another or with chemotherapy will better the cure rate of patients with Philadelphia chromosome-positive ALL and pre B-cell ALL.

Transcription:

0:08 | In acute lymphocytic leukemia, I think there's now a paradigm shift in the cytopathic approaches. This is because we started introducing targeted therapies like the BCR-ABL tyrosine kinase inhibitors in Philadelphia-positive acute lymphocytic leukemia, as well as introducing the antibodies targeting CD19 and CD22.

0:32 | In Philadelphia-positive acute lymphocytic leukemia, using the third generation TKIs like ponatinib in combination with blinatumomab, which is a CD19 bispecific T-cell engager, we found that we can induce almost all patients in remission. The estimated 2 year survival is over 90%, and we are not needing to send the patients to transplant. We have shifted from a combination of intensive chemotherapy with first and second generation TKIs and relying on allogeneic transplantation to a strategy that has no chemotherapy, no need for transplant, and a very high cure potential.

1:17 | In pre B-cell acute lymphocytic leukemia, we introduced both blinatumomab and inotuzumab into the frontline therapy with less chemotherapy. We again found that almost all patients achieved a complete remission, and at 3 to 4 years, their estimated survival is over 80%, which is the first time that we've seen such survivor rates at MD Anderson. I'm hoping that 5 years from now, there's going to be a therapeutic revolution in ALL instead of giving 3 years of intensive chemotherapy in adults and older patients. I hope for a cure rate of 40- 50% so we will be able to give the newer regimens and double the cure rate to levels which are similar to childhood ALL.

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Evolving Treatment Landscape of Acute Lymphocytic Leukemia - Targeted Oncology

To make the discovery, the team used brand new technology to devise a technique that enables them to see and study the electrical properties of brain cell interactions, which could not be observed previously.

With these new tools, we've essentially uncovered completely novel aspects of the biology," says Armbruster, research assistant professor of neuroscience at the School of Medicine. As better tools come alongfor example, new fluorescent sensors are being developed constantlywe'll get a better understanding of things we didn't even think about before.

The new technology images electrical activity with light, Dulla explains. Neurons are very electrically active, and the new technology allows us to see that astrocytes are electrically active, as well.

Dulla describes astrocytes as making sure everything is copacetic in the brain, and if something goes wrong, if theres an injury or viral infection, they detect it, try to respond, and then try to protect the brain from insult. What we want to do next is determine how astrocytes change when these insults happen.

Neuron-to-neuron communication occurs through the release of packets of chemicals called neurotransmitters. Scientists knew that astrocytes control neurotransmitters, helping to make sure that neurons stay healthy and active. But the new study reveals that neurons also release potassium ions, which change the electrical activity of the astrocyte and how it controls the neurotransmitters.

So the neuron is controlling what the astrocyte is doing, and they are communicating back and forth. Neurons and astrocytes talk with each other in a way that has not been known about before, he says.

The discovery of astrocyte-neuron crosstalk raises numerous questions as to how the interactions work in brain pathology and in the development of learning and memory. It makes us rethink everything astrocytes do, and how the fact that astrocytes are electrically active may be influencing a wide range of neurological diseases, he says.

For example, in Alzheimers disease, astrocytes dont control neurotransmitters, even though that is their fundamental job, Dulla explains. Similar problems occur with traumatic brain injury and epilepsy. For years scientists have thought perhaps the problem is caused by a protein being absent, or a mutation that causes a protein not to work.

Build-up of extracellular potassium in the brain, has been hypothesized to contribute to epilepsy and migraine pathologies, says Armbruster. This new study gives us a better understanding of how astrocytes clear this buildup and help maintain a balance of excitation.

The researchers are now screening existing drugs to see if they can manipulate the neuron-astrocyte interactions. By doing so, can we one day help people learn faster or better? Can we repair a brain injury when it occurs? Dulla asks.

The new technology used to make this discovery not only opens up new ways to think about astrocyte activity, it also provides new approaches for imaging activity through the brain. Before now, there was no way to image potassium activity in the brain, for example, or study how potassium is involved in sleep, metabolism, or injury and infection in the brain.

We are giving these tools to other labs so they can use the same assays and techniques to study the questions they are interested in, he says. Scientists are getting the tools to study headache, breathing, developmental disorders, and a wide range of different neurological diseases.

View original post here:
Tufts Researchers Discover New Function Performed by Nearly Half of Brain Cells - Tufts Now

April 27, 2022

In breakthrough research at ChristianaCares Helen F. Graham Cancer Center & Research Institute, scientists have discovered that a protein secreted by tumor cells can switch off the bodys natural defenses against triple negative breast cancer (TNBC).

The study, led by Jennifer Sims-Mourtada, Ph.D., lead research scientist at the Cawley Center for Translational Cancer Research (CTCR), at the Graham Cancer Center, is reported in The Journal of Translational Medicine which is available online.

What we found is that TNBC tumor cells can effectively shut down the bodys defense systems against the tumor by secreting a type of protein called IL-10, Dr. Sims-Mourtada said.

The presence of this immune system protein forces the antibodies that would normally be created to attack the tumor to become non-reactive and not do what they are supposed to do.

The study was initiated in partnership with The Wistar Institute of Philadelphia, Pennsylvania, in collaboration with the late Raj Shyam Somasundaram, Ph.D., a cell biologist at the Melanoma Research Center.

Dr. Sims-Mourtada and her team have brought us tantalizingly close to understanding what drives the aggressive nature of triple negative breast cancer, a treatment-starved disease that disproportionately affects Delaware women, said Nicholas J. Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute.

Their work underscores our belief that scientific collaborations such as this one between our Cawley CTCR clinicians and Wistar scientists can smooth the way for new findings to become effective therapies, especially for hard-to-treat and aggressive forms of cancer like TNBC.

Understanding the mechanism behind TNBC

Delaware ranks highest in the nation for incidence of triple negative breast cancer. TNBC is an aggressive form that affects Black women at twice the rate of white women with poorer outcomes. Patients have higher rates of early recurrence than other breast cancer subtypes, particularly in the first five years after diagnosis. Currently there is no targeted therapy for TNBC.

One of our missions within the Cawley CTCR is to understand the mechanisms behind TNBC and find a treatment for it, Dr. Sims-Mourtada said. Our study sheds new light on what is prompting the bodys immune response to the cancer cells and offers clues to potential new therapeutic targets.

Normally it is the job of the B cells to regulate the immune response against foreign invaders like cancer. Among other jobs, they control inflammation at the site of an attack by releasing proteins, including IL-10, to signal the defender cells to stand down.

Previously it was thought that the immune cells were the ones to express IL-10 to regulate themselves, Dr. Sims-Mourtada said. But our study shows that the tumor cells also release this protein, which means they are driving how the immune system behaves.

Within the tumor microenvironment, IgG4 is one of four antibody subclasses expressed and secreted by B cells. Whereas another type of antibody would urge the immune system to press on with the attack, activation of IgG4 signals the job is done.

TNBC and activation of IgG4

Our findings support that TNBC may create a tumor environment that supports activation of IgG4, and messaging from IL10 is triggering the switch, Dr. Sims-Mourtada said.

As previously reported with other cancers, such as melanoma, this study confirms that the presence of IgG4-positive B cells within the tumor associates with advanced disease increased recurrence and poor overall breast cancer survival. It is also possible that IL-10 expression by tumor cells may also be a cause of poor outcomes in TNBC, and this may be independent of IgG4+ B cells.

At this point, we dont know what causes tumor cells to start secreting IL-10, but we know that B cell-tumor cell interactions are involved, Dr. Sims-Mourtada said.

We still have to look at what is really going on in the B cell population to determine which subtypes of B cells are affected by this tumor crosstalk and why some forms of TNBC express IL-10 (the ones with poor outcomes) and others do not.

We think that the presence or absence of other immune cells in the microenvironment may affect how B cells interact with tumor cells to drive IL-10 expression, she said.

Resources for the study, including blood and tissue samples from consenting patients, were obtained through the Graham Cancer Centers Tissue Procurement program. Interestingly, in a small subset of samples, the researchers found that IL-10 expression was significantly higher in Black patients than non-Hispanic white patients. These findings need to be confirmed in a larger more diverse population with different TNBC subtypes.

Understanding tumor-infiltrating B cells

Our growing understanding of the contribution of IgG4+ cells to the immune microenvironment of TNBC and what drives IL-10 expression may reveal ways in which tumor-infiltrating B cells can contribute to tumor growth and provide new targets to increase the immune response to TNBC, Dr. Sims-Mourtada said.

As partners for more than a decade, Graham Cancer Center research clinicians and Wistar scientists collaborate across disciplines to translate cancer research into more effective therapies for patients everywhere. In addition to providing high-quality, viable tissue samples for Wistar research studies, Graham Cancer Center clinicians actively participate in concept development, sharing their unique understanding of the everyday patient experience.

Original post:
New Research: Tumor Cells Can Manipulate the Body's Natural Antibody Response to Triple Negative Breast Cancer - ChristianaCare News

Innate immune memory can cause one type of inflammatory conditionfor example, gum diseaseto increase susceptibility to anotherlike arthritis. Now, new findings show that alterations to immune cell precursors in the bone marrow underlie the mechanism that forms the connection.Using a mouse model, the team demonstrated that recipients of a bone marrow transplant were predisposed to more severe arthritis if their donor had inflammatory gum disease.

This work is published in Cell in the article, Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.

Although we use periodontitis and arthritis as our model, our findings go above and beyond these examples, said George Hajishengalliis, DDS, PhD, professor at the University of Pennsylvania School of Dental Medicine. This is in fact a central mechanism, a unifying principle underlying the association between a variety of comorbidities.

In previous work, Hajishengallis and colleagues explored the role of innate immune memory. Their findings showed that the innate immune systems myeloid cells, such as neutrophils and macrophages, could remember past encounters, becoming more responsive when exposed to a new threat. The work also showed that this trained immunity could be transferred from one organism to another through a bone marrow transplant, protecting recipients from cancer through an innate immune response.

The researchers hypothesized that this trained immunity could be detrimental in the right contexts. The thoughts went like this: We knew the gum disease periodontitis increased the risk of comorbidities like cardiovascular disease, said Hajishengallis. And the reverse is also true: People with the inflammatory disease colitis, for example, have an increased prevalence of periodontal disease. Different mechanisms have been proposed, but no one unifying mechanism could explain this bidirectionality.

The scientists sought the source of the association between comorbidities to the innate immune training they already knew was happening in the bone marrow.

The team showed that, within a week of inducing a mouse to have periodontal disease, the animals myeloid cells and their progenitor cells expanded in the bone marrow. Examining these cells weeks later, after periodontitis was intentionally resolved, the researchers did not notice significant changes in how the cells looked or behaved.

However, these progenitor cells appeared to have memorized the inflammation they were exposed to, as they harbored important epigenetic changes. The researchers found that these alterations, triggered by inflammation, could alter the manner in which the genes would be expressed after a future challenge. The overall pattern of epigenetic changes, the researchers noted, was associated with known signatures of the inflammatory response.

Mice with induced periodontal disease also had more severe responses to a later immune system challenge, evidence of trained immunity.

To put the whole picture together regarding the link between inflammatory conditions, the critical experiment, as Hajishengallis explained, was a bone marrow transplant. Mice that had periodontitis, a severe form of gum disease, served as donors, as did a group of healthy mice serving as controls. Two hundred stem cells from their bone marrow were transplanted into mice that had never had gum disease and which had had their own bone marrow irradiated. A few months later, these mice were exposed to collagen antibodies, which trigger arthritis.

Mice that received the transplant from mice with periodontitis developed more severe arthritis than mice that received a donation of stem cells from periodontally healthy mice, said Hajishengallis. In addition, higher joint inflammation in recipient mice was due to inflammatory cells deriving from the periodontitis-trained stem cells.

Further experiments suggested that the signaling pathway governed by a receptor for IL-1 played a vital role in contributing to this inflammatory memory. Mice that lacked IL-1 receptor signaling could not generate the immune memory that made the recipient mice more susceptible to comorbidities.

The work underscores that blocking IL-1 receptor signaling could be an effective approach to mitigate against these knock-on effects of trained immunity. Weve seen anti-IL-1 antibodies used in clinical trials for atherosclerosis with excellent results, Hajishengallis said. It could be that it was in part because it was blocking this maladaptive trained immunity.

Follow-up projects are examining how other inflammatory conditions, may be linked with periodontal disease, a sign, the researchers said, of how crucial oral health is to overall health.

See more here:
Inflammation in Gum Disease and Arthritis Linked by Bone Marrow Immune Cells - Genetic Engineering & Biotechnology News

ByMichael Newman

New research may explain why so many vaccinated and boosted individuals experienced breakthrough coronavirus infections caused by the omicron variant. Researchers at Johns Hopkins Medicine and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health have uncovered evidence that while fully vaccinated and boosted people produce a high level of antibodies that work against the original strain of SARS-CoV-2, the same tiny defenders don't do as well in preventing the omicron strain from attacking healthy cells.

The research findings were posted online in the Journal of Clinical Investigation Insight.

"Previous research has shown vaccine-induced antibodies respond to the original strain of SARS-CoV-2 by inhibiting the virus's ability to bind to angiotensin-converting enzyme 2 [commonly known as ACE2], the receptor on a cell's surface through which SARS-CoV-2 gains entry," says study senior author Joel Blankson, professor of medicine at the Johns Hopkins University School of Medicine. "Our study suggests those same antibodies yield less ACE2 inhibition with the omicron strain, opening the door to a breakthrough COVID-19 infection."

Joel Blankson

Professor, Johns Hopkins School of Medicine

To conduct their study, Blankson and his colleagues analyzed two types of immune responses to SARS-CoV-2: the humoral immune response, marked by virus-specific antibodies circulating in the bloodstream and produced by B lymphocytes, or B cells; and the cellular immune response, which is a direct attack on the virus by T lymphocytes, or T cells. Researchers observed these immune responses in 18 healthy and fully vaccinated people, ages 23-62, who experienced breakthrough infections within 14 to 92 days after receiving a booster COVID-19 vaccine. Of the participants, 14 received a booster of the Pfizer-BioNTech mRNA vaccine, one was boosted with the Moderna mRNA vaccine, and the remaining three had an mRNA booster following their initial dose of the Johnson & Johnson viral vector vaccine.

The humoral and cellular immune responses of those participants with breakthrough infections were compared with those from a control group of 31 participants, ages 21-60, who received similar COVID-19 vaccinations and boosters and had no prior infection with SARS-CoV-2.

Although the researchers were not able to document that the breakthrough infections were from the omicron strain, they say it's a strong probability because the omicron variant accounted for more than 90% of the COVID-19 cases treated at the Johns Hopkins Hospital, where the study was conducted, during the time when the study participants became symptomatic.

Coverage of how the COVID-19 pandemic is affecting operations at JHU and how Hopkins experts and scientists are responding to the outbreak

"When we tested antibody-mediated inhibition of SARS-CoV-2 spike protein binding to ACE2, we found that serum from study participants with breakthrough COVID-19most likely the result of omicron infectionhad antibodies that strongly stopped binding by the original strain virus as expected but didn't carry out that function as well when responding to the omicron strain," says Blankson.

The specific reduction in ACE2-inhibiting antibodies responding to omicron, Blankson says, differs from what was seen in previously studied breakthrough infections with the alpha variant. In those cases, infected individuals were found to have lower overall antibody levels to the original virus strain. The levels of antibodies that inhibited the spike protein binding to ACE2high for the original strain of the virus but reduced for omicronwere similar for both the participants with breakthrough infections and those in the control group.

Moreover, the level of cellular immunityas measured by the amount of responding T cells documentedremained strong in the breakthrough and control groups for both the original and omicron strains. This was shown in a second recent study, also co-authored by Blankson, looking at the blood plasma of 15 mRNA vaccine recipients.

"The comparable strong T cell responses for the original and omicron strains in both studies could explain why people, like our study participants, who have breakthrough COVID-19 cases typically experience only mild symptoms during the course of their illness," he explains.

Read more:
Antibodies fighting original virus may be weaker against omicron - The Hub at Johns Hopkins

MORGANTOWN, W.Va. -- A new data-driven mechanistic approach that predicts cell types within tissue will help to reduce drug costs and treat diseases that were difficult to develop drugs for, according to a West Virginia University scientist.

David Klinke, professor in the Department of Chemical and Biomedical Engineering, developed and tested a mechanistic approach to predict the number and function of different cell types within a particular tissue and how they change when a malignant (cancerous) cell acquires the ability to secrete a protein.

Ultimately, we want to develop drugs that broaden the clinical benefit of immunotherapies, said Klinke, whos also an adjunct assistant professor in the WVU School of Medicine and member of the Cancer Institute.

Mechanistic models have been created by hand by experts, but there are gaps in researchers understanding of biology because 90% of research publications focus on only 20% of genes in humans.

Research from this study, published in Nature Communications, sifts through large datasets to predict how secretion of one gene product by a malignant cell influences other cell types within a tissue directly from the data. This provides a complement to the hand-created models that play important roles in drug development.

Under normal conditions, ones immune system defends against infectious disease, Klinke said. However, most cancers arise through an evolutionary process of mutation and selection. Every cell has the blueprint in its DNA to make every gene product. In that process of mutation and selection, re-expression of some of these gene products may provide malignant cells with the ability to suppress immune response.

Human tissues are made up of specialized cell types that are organized to maintain function in a changing environment. Ultimately, the functional orientation of cell types within a tissue interact to create a heterocellular network -- a network of many different cell types that interact to collectively achieve a goal. A heterocellular network is important to create and maintain tissue equilibrium.

While researchers know that tissue equilibrium is disrupted during oncogenesis, or the development of a tumor, there is no clear understanding of how genetic alterations influence the heterocellular network within human tissues.

Klinke said one of the barriers for broadening clinical benefit is that malignant cells create environments that suppress host immunity.

This new data-driven approach allows researchers to predict how a gene product secreted by a malignant cell changes the prevalence and functional orientation of other cell types within a human tissue.

Klinke said that studying how one event causes another is challenging to do in systems where it's difficult for researchers to see what is happening like within an intact human tissue.

To test their predictions, using digital cytometry and Bayesian network inference, Klinke and his team examined immunocompetent mouse models of cancer. With this approach, Klinke was able to predict how a protein secreted by malignant cells alters the heterocellular network in the context of melanoma and breast cancer.

Digital cytometry, which is the measurement of the number and characteristics of cells, and Bayesian network (a probabilistic graphical model) inference were used because there are datasets available with these models that contain sequenced homogenized (similar) tumor tissue.

We can change the expression of a gene and then see whether the prevalence and functional orientation of different cell types in the tumor changes similarly as predicted by the Bayesian network model.

Klinke said the conventional approach to predict the functional orientation of cell types is to change the expression of a secreted protein and then quantify different cell types using different experimental approaches.

For this study, Klinke used mechanistic modeling to represent the mechanisms that support the biology and predict scenarios using simulation instead of actually testing the scenario in humans.

These models are highly complicated but let me use a simple analogy, Klinke said. Say that we want to hit a target using an artillery shell and we have only one shot. Given our understanding of the laws of physics, we know that we need to know a few things about the projectile and all the forces acting on the projectile. Given this information, we can simulate with a computer that if we fire the projectile in a certain direction or angle, it will land in a certain location.

Similarly, we know a lot about the underlying biology associated with a drug, but there are also some things that we dont know, and we cant test everything in humans. Given common conversations in the media about the high price of drugs, testing new drugs in humans is expensive and the vast majority of new drugs tested dont work.

Klinke said that one of the ways that mechanistic modeling and simulation can help is by providing a way to bring all the different pieces of understanding together in the same context.

If there are key aspects missing, we run simulations to see if targeting some aspect of the biology with a drug makes sense. Mechanistic modeling and simulation have had an impact on a number of other industries, and this is now being applied to drug development.

Klinke hopes that this research can be used in other contexts like cancers or immunologic diseases.

Ultimately, we all care that when we get sick, there are treatments that can improve our health and not bankrupt us in the process. Like many other industries, the pharma industry is turning increasingly to mechanistic modeling and simulation to better prioritize potential targets and reduce the time to clinic. Collectively, this will help reduce drug costs and help treat diseases that were difficult to develop drugs for.

Citation: Data-driven learning how oncogenic gene expression locally alters heterocellular networks

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WVU researcher develops data-driven approach to help reduce drug costs and treat diseases - West Virginia University

Scientists at Sinai Health and the University of Toronto say a new drug designed to block an enzyme essential for the survival of certain cancer cells shows promise in curbing tumour growth.

The preclinical findings,published this month in the journalNature, describe a new drug designed with CRISPR-Cas9 gene-editing technology in the lab ofDaniel Durocher, a senior investigator at Sinai HealthsLunenfeld-Tanenbaum Research Institute(LTRI) and a professor ofmolecular geneticsin U of Ts Temerty Faculty of Medicine.

The researchers identified genes that are essential for the viability of CCNE1 amplified cancer cells, which are characteristic of some hard-to-treat ovarian, endometrial and bladder cancers. They found the enzyme PKMYT1 is essential in CCNE1 amplified cells, but not in otherwise healthy cells. In collaboration with precision oncology companyRepare Therapeutics, the team developed a drug called RP-6306, which blocks PKMYT1 activity and effectively kills the cancer cell.

These cancer cells depend on the PKMYT1 enzyme to survive, said Durocher. Our preclinical data show enormous promise in the drug RP-6306s ability to target these types of tumours and profoundly inhibit tumour growth.

Currently, tumors with CCNE1 amplification have very few therapeutic options.David Gallo, a senior scientist at Repare Therapeutics, said theyve been able to demonstrate that RP-6306 is both potent and selective for oral use in humans.

Gynecological and other solid tumours with amplifications of CCNE1 are notoriously resistant to current standard-of-care treatments, said Gallo, co-first author on theNaturepaper. There is a dire need to find new options for these patients.

The work was a close collaboration between the Durocher lab and Repare Therapeutics. Durocher founded Repare Therapeutics in 2016 alongsideFrank Sicheri, also aLunenfeld-Tanenbaum Research Institute senior investigator who is a professor of molecular genetics andbiochemistryat U of T.

The company is built on the concept of synthetic lethality, a process that incorporates functional genomics to discover genetic vulnerabilities to specific cancer mutations.

This close collaboration between our group and Repare highlights how industry and academia can work together to discover new treatment options for cancer patients,said Durocher. Its rare that a new target is published alongside a launched clinical trial. This speaks volumes about the innovative capacity of the LTRI and its collaborators.

Repare Therapeutics has initiated Phase I clinical trials in patients with CCNE1 amplified solid tumours, with initial results expected in late 2022.

The research was funded by Repare Therapeutics and the Canadian Institutes of Health Research.

This story was originally published at Sinai Health.

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New drug shows promise slowing tumour growth in some hard-to-treat cancers - University of Toronto

image:Artificial heart tissue can contract against a resistance and then relax. view more

Credit: Michael Gotthardt, MDC

The contractile and elastic properties of the heart are finely tuned. This is a prerequisite for the cardiac cycle and efficient adaptation. At the MDC, Michael Gotthardt investigates the underlying molecular and biomechanical mechanisms. He is awarded with an ERC Advanced Grant for this work.

MERAS is the acronym on the recently approved project proposal. It stands for: Mechanoregulation of alternative splicing. We would like to understand how the heart responds to environmental factors and adjusts its elastic properties such that it can function at an optimal level, says Michael Gotthardt. He heads the research group Neuromuscular and Cardiovascular Cell Biology at the Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC). For his project, he now receives an Advanced Grant of 2.5 million from the European Research Council (ERC).

This ERC Advanced Grant is awarded to scientists with more than ten years of research experience who have already played a prominent role in their field. Out of the 1,735 researchers from across Europe who applied for the grants this year, 253 were successful.

The mechanical work of the heart depends on the sarcomere, the smallest contractile unit. Here, actin and myosin filaments facilitate contraction, while the giant protein titin determines the elastic properties of heart muscle cells. Different titin variants (isoforms) are expressed perfectly adapted to the mechanical needs. The researchers wish to investigate the underlying process alternative splicing in detail.

Refined regulatory feedback

Our recent analysis of sarcomeric protein composition not only identified the expected structural proteins, but also proteins that link to cell signalling, metabolism, the regulation of gene expression and alternative splicing. These are proteins you would normally expect in the nucleus but not in the sarcomere, emphasizes Michael Gotthardt. It appears that the sarcomere directly communicates with the nucleus on necessary adaptations. The unexpected feedback from sarcomere to spliceosome could explain how sarcomeres adjust to mechanical stress. This is a new hypothesis that the researchers will explore in depth.

A detailed understanding of the regulatory process could also have therapeutic relevance e.g. for people with heart failure. For most of these patients, the ventricular walls have become so rigid that the chambers are no longer able to fill sufficiently. A drug that interferes with the communication from sarcomere to spliceosome could make a stiff cardiac ventricle more compliant, resulting in more efficient filling.

A second ERC grant

This year, the ERC selection process was not solely based on the submitted proposals, but for the first time included short presentations online of course due to Covid 19. Four slides in eight minutes for a 2.5 million euro project, recounts Michael Gotthardt, who is also Professor of Experimental and translational cardiology at Charit Universittsmedizin Berlin. For the scientist, this is already the second substantial contribution from the EU following his ERC Starting Grant in 2011. It extends over a period of five years. This enables us to build up lasting collaborations and projects with extended time lines. And deep sequencing as a prerequisite to evaluate alternative splicing at scale would otherwise be prohibitively expensive.

Gotthardts team works with genetic mouse models, synthetic heart tissue derived from patient cells and isolated heart muscle cells (cardiomyocytes). Single cell mechanics is precision work. For this, the cardiomyocytes first need to be isolated, secured under a special microscope and electrically stimulated. Then you can derive the active and passive forces, says Michael Gotthardt. This would provide the properties of just one single cell. However, for a convincing study, a large number of these experiments need to be conducted.

The goal: new technologies for single-cell mechanics and multi-omics

Extensive manual work is also required to understand which titin isoforms are expressed in response to stress or disease. Compared to a large piece of tissue, a single cell contains relatively few RNA molecules which means that analysis of gene expression frequently reaches the detection limit.The analysis of alternative splicing is even more difficult for giant titin isoforms with up to 100,000 bases. Here, available short reads need to be assembled like a jigsaw puzzle that misses important pieces, says Michael Gotthardt. With the ERC funding, among other things, he plans to develop technologies for single cell mechanics, -transcriptomics, -proteomics that will facilitate multi-omics approaches and enable higher rates of throughput.

The Max Delbrck Center for Molecular Medicine (MDC)

The Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC) is one of the worlds leading biomedical research institutions. Max Delbrck, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the MDCs locations in Berlin-Buch and Mitte, researchers from some 60 countries analyze the human system investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The MDC therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charit Universittsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC ), the Berlin Institute of Health (BIH) at Charit, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the MDC today employs 1,600 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.www.mdc-berlin.de

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ERC Advanced Grant for cardiac research at the MDC - EurekAlert