Category Archives: Cell Medicine

A randomized, double blind human clinical trial conducted by researchers at Baylor College of Medicine reveals that supplementation with GlyNAC a combination of glycine and N-acetylcysteine improves many age-associated defects in older humans and powerfully promotes healthy aging. This is relevant because until now, there have been no solutions toward improving many of these age-related declines in people.Published in the Journalof Gerontology: Medical Sciences, the study shows that older humans taking GlyNAC for 16-weeks improved many characteristic defects of aging. This includes oxidative stress, glutathione deficiency and multiple aging hallmarks affecting mitochondrial dysfunction, mitophagy, inflammation, insulin resistance, endothelial dysfunction, genomic damage, stem cell fatigue and cellular senescence. These were associated with improvements in muscle strength, gait speed, exercise capacity, waist circumference and blood pressure.

This is the first randomized clinical trial of GlyNAC supplementation in older humans, and it found that a wide variety of age-associated abnormalities improved in older adults supplemented with GlyNAC, while no improvements were seen in those receiving placebo, said corresponding author Dr. Rajagopal Sekhar, professor of medicine - endocrinology, diabetes and metabolism at Baylor.

The improvements in oxidative stress, glutathione levels and mitochondrial function in the muscle tissue of older humans taking GlyNAC were similar to the improvements in organs such as the heart, liver and kidneys of aged mice supplemented with GlyNAC as reported in the researchers recent publication. Taken together, the results of these studies show that GlyNAC supplementation can improve these defects in many different organs of the body. GlyNAC supplementation in aging mice increased their length of life mice by 24%, said Sekhar. Gait speed is reported to be associated with survival in older humans. Our randomized clinical trial found a significant improvement in gait speed in older humans supplemented with GlyNAC. This raises the interesting question of whether GlyNAC supplementation could have implications for survival in people.For the last 20 years, Sekhar has been studying natural aging in humans and animal models to understand why age-related declines occur and how to correct them. His work brings mitochondria, known as the batteries of the cell, as well as free radicals and glutathione to discussions about how they are connected. Sekhars work and discoveries could also help explain why we age and how to improve health while aging.

Mitochondria dysfunction, oxidative stress and aging

Mitochondria generate energy needed for supporting cellular functions. Therefore, normal mitochondrial function is critically important for a healthy life. Sekhar believes that improving the health of malfunctioning mitochondria in aging is the key to healthy aging. Energy supports life and mitochondria provide energy. I believe that mitochondrial health is vitally important to our well-being, and maintaining mitochondrial health as we age should be a high priority in our efforts to improve overall health, said Sekhar.

However, the ability of mitochondria to work well declines as we age. How to improve the ability of these failing mitochondria to work is not well understood, and therefore no solutions have been available. Sekhars group discovered earlier that supplementing GlyNAC in aged mice corrected malfunctioning mitochondria. However, to definitively determine whether GlyNAC supplementation benefited people, a placebo-controlled randomized clinical trial was required.

Sekhar and his team conducted and completed such a randomized clinical trial which found that older people have widespread mitochondrial damage and other age-associated defects compared to young people. After 16-weeks of GlyNAC supplementation, mitochondrial function of older people improve toward levels found in young people. This was accompanied by improvements in multiple additional outcomes as reported in the publication. Analysis of the molecular data from the trial suggests that the GlyNAC supplementation is able to fill cells with younger and more efficient mitochondria. Collectively these exciting new discoveries hold great promise for improving our mitochondrial and general health as we age, Sekhar said.

A second vital benefit offered by supplementing GlyNAC is that it also helps protect the body from an important problem called oxidative stress. Oxidative stress is caused by high levels of toxic waste products known as reactive oxygen species or free-radicals. Oxidative stress can damage our cells, membranes, lipids, proteins and DNA, and is very common in aging. Glutathione is a natural antioxidant. Glutathione is made every day inside our cells and it works by protecting cells from harmful oxidative stress. However, in older people, glutathione levels are very low and the harmful oxidative stress is very high. GlyNAC supplementation corrects glutathione deficiency and lowers oxidative stress in older humans back to youthful levels, thereby solving both problems.

Sekhar believes that the restoration of mitochondrial health and correction of oxidative stress with GlyNAC supplementation are two powerful reasons which help explain why so many other age-related defects improve. It also accounts for the wide spectrum of health benefits.

Taking GlyNAC is not the same as taking glutathione: Introducing the Power of 3

It is really important to understand that this trial supplemented GlyNAC, and did not supplement glutathione, says Sekhar. This is because our body does not get its glutathione from food, but the body has to make its own glutathione every day. All our organs maintain different levels of glutathione in a delicate balance that favors health. Too little glutathione cannot fight the harmful oxidative stress, and too much glutathione could lead to harmful reductive stress, said Sekhar. This is why GlyNAC is a natural solution for correcting glutathione deficiency, because it provides the raw materials to help cells to make their own glutathione in just the right amount. We have seen that this repeatedly in all our prior studies supplementing GlyNAC, including this trial.

One of the intriguing questions from this trial is why so many improvements occur toward promoting health. We believe that this is due to the combined effort of three separate components glycine, cysteine (from NAC) and glutathione, and not just due to glutathione itself. Glycine and cysteine are both very important for cellular health on their own, and GlyNAC provides both. Glycine and cysteine are building blocks to form glutathione, which also has health benefits. We believe that the improvements in this trial and in our previous studies are the result of the combined effects of glycine and NAC and glutathione, and we refer to this combination as the Power of 3, said Sekhar.

GlyNAC improves several aging hallmarks in agingThe population of older adults is expected to exceed 2.1 billion by 2050, according to the World Health Organization. This predicted increase in the older human population will result in a rise of the need for healthcare and will intensify the stress on healthcare systems around the world. To understand what causes unhealthy aging, scientific research has identified nine aging hallmarks that represent specific defects that are believed to contribute to health decline while aging.

It is believed that correcting aging hallmarks could help people age in a healthier way, Sekhar said. However, we do not fully understand why these aging hallmarks occur in the first place, and therefore there have been no proven solutions via human randomized clinical trials to improve or correct aging hallmarks in aging humans.

The aging hallmarks that improved are mitochondrial dysfunction, altered intercellular communication, nutrient sensing, loss of proteostasis, genomic instability, cellular senescence and stem cell fatigue. The study participants were instructed not to change their usual diet or physical activity; therefore, nothing changed except for the GlyNAC supplementation. This tells us that benefits were due to GlyNAC supplementation. But we were really surprised to see so many aging hallmarks improve. This level of improvement offers clues as to how and why these aging hallmarks may be connected to one another, says Sekhar.

GlyNAC improves muscle strength in aging

GlyNAC supplementation improved muscle strength in the upper and lower extremity and a trend toward increased exercise capacity. These findings could have additional implications for improving the health of older humans, especially in terms of being able to be more physically active, said Sekhar.

This study was effort intensive and took many years to complete. I take this opportunity to thank all my co-investigators, nursing staff, and everyone who helped with this trial. I especially thank all the trial participants who volunteered to participate in this research, Sekhar said.

Sekhar led the study team consisting of Premranjan Kumar, Chun Liu, James Suliburk, Jean W. Hsu, Raja Muthupillai, Farook Jahoor, Charles G. Minard and George E. Taffet, all at Baylor College of Medicine. For this trial, Sekhar received funding support from the National Institutes of Health/National Institute of Aging, and philanthropic support from the McNair Medical Institute at the Robert and Janice McNair Foundation in Houston, TX.

Baylor College of Medicine holds a patent on GlyNAC, which has been licensed to Nestl Health Science. GlyNAC is marketed in the United States by Nestl Health Science under the nameCelltrientTM Cellular Protect. Nestl Health Science did not provide financial or material support for this research work.

As he moves forward, Sekhar plans to expand on his work to understand more about the health benefits of GlyNAC supplementation on cells, tissues and organs of the body. He plans on seeking funding to conduct larger clinical trials in more typical older humans to increase our understanding of how GlyNAC could improve health in aging. Additionally, as reported in their previously published exploratory study, Sekhars group found that GlyNAC supplementation in older humans could improve memory and cognition. He has studied this further in aged mice and found that GlyNAC supplementation appears to correct multiple age-related declines directly in the brain, and was associated with improvements in memory and brain health a report on these emerging new and exciting findings is in development.

The Journals of Gerontology Series A

Randomized controlled/clinical trial

People

Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial

17-Aug-2022

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GlyNAC supplementation reverses mitochondrial dysfunction, oxidative stress and aging hallmarks to boost strength and promote health in aging humans -...

BOSTON Researchers at Massachusetts General Hospital (MGH), published a new paper in Cell Reports Medicine demonstrating the protective potential of multiple doses of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 and other infectious diseases.

In a double-blind, placebo-controlled study of patients with type 1 diabetes conducted at the start of the pandemic (before COVID-specific vaccines were available), the researchers found that 12.5% of placebo-treated individuals and 1% of BCG-treated individuals met criteria for confirmed COVID-19, yielding a vaccine effectiveness of 92%.

The BCG-vaccinated group also displayed protective effects against other infectious diseases, including fewer symptoms, lesser severity and fewer infectious disease events per patient. No BCG-related systemic adverse events occurred.

BCGs broad-based infection protection suggests that, in addition to COVID-19, may potentially provide protection against new SARS-CoV-2 variants and other pathogens.

The researchers are hoping the results will spur a larger scale study of the effects of the BCG vaccine in patients with type 1 diabetes, considered among the most vulnerable groups to COVID-19.

The BCG vaccine is an avirulent tuberculosis strainMycobacterium bovishistorically given to protect against tuberculosis and, since its introduction in 1921, has been the most widely administered vaccine in the history of medicine.

Considered to be extremely safe, BCG is on the World Health Organizations List of Essential Medicines and is given to roughly 100 million children per year globally. BCG is also one of the most affordable medicines, costing less than a dollar a dose in many parts of the world.

Multiple studies have shown that adults with type 1 diabetes who are diagnosed with COVID-19 are at increased risk of severe illness.

We found that three doses of BCG administered prior to the start of the pandemic prevented infection and limited severe symptoms from COVID-19 and other infectious diseases.

Unlike the antigen-specific vaccines currently in use to prevent COVID-19, BCGs mechanism of action is not limited to a specific virus or infection, says Denise Faustman, MD, PhD, director of theImmunobiology Laboratoryat Massachusetts General Hospital.

The participants in the COVID trial had previously enrolled in a clinical trial testing the effectiveness of the BCG vaccine for type 1 diabetes. Participants in the test group had received multiple vaccinations prior to the onset of the pandemic in early 2020.

This data set is unique and exciting because the patients were all vaccinated with multiple doses of BCG prior to the onset of the epidemic. Prior to the trial they had no known exposure to tuberculosis or prior BCG vaccination. This eliminates the major confounding factors that have limited other trials.

The results support the idea that BCG needs time to have a clinical effect, but its effects may then be very lasting and durable saysHazel Dockrell, London School of Hygiene & Tropical Medicine, an infectious diseases expert who was not officially involved in the study.

The 144 adult type diabetics (96 BGC treated and 48 placebo) analyzed in the COVID-19 trial were part of an ongoing Phase IIb clinical trial testing BCG as a treatment for adults with established type 1 diabetes. Patients were followed for COVID-19 related outcomes for 15 months.

Outcomes for the COVID-19 trial included: COVID-19 infection rate, COVID-19 related symptoms, reduction overall infections disease and SARS-CoV-2 antibody-level presence and intensity. The type 1 diabetes outcomes were not unblinded as part of this study and will be unblinded at the completion of the trial in 2023.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. TheMass General Research Instituteconducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #5 in theU.S. News & World Reportlist of Americas Best Hospitals.

Cell Reports Medicine

Randomized controlled/clinical trial

People

Multiple BCG vaccinations for prevention of COVID-19 and other infectious diseases in Type 1 diabetes

15-Aug-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Multiple shots of the BCG vaccine protect type 1 diabetics from COVID-19 - EurekAlert

As per the latest report published by Future Market Insights, a leading Market Research firm, the Cell Regeneration Medicines Market is valued at US$ 30.3 Bn and is anticipated to reach the valuation of US$ 34.3 Bn by the end of 2032 by growing at a CAGR of 14.4%. The compound annual growth rate for the forecasted period is significantly higher from the historic CAGR of 12.4%. Furthermore, the market is expected to offer an absolute dollar opportunity of US$ 96.5 Bn in the upcoming 10 years.

The Therapeutics segment generated the most revenue in the Global Cell Regeneration Medicines Market in 2021. Revenue through this category is expected to grow at a CAGR of 16.5% during the period between 2022 and 2032. This can be attributed to higher adoption of primary cell-based therapies in clinical application and their increased usage in different therapeutic indications.

The market expansion is attributed to the introduction of gene therapy, along withadvancements in stem cell and tissue engineering. The presence of several programmes and ongoing funding in R&D by government and commercial entities help towards the market development.Additionally, the regulatory approvals in this field are further clearing the present roadblocks in the market growth.

In addition, the Global Cell Regeneration Medicines Market considers Oncology to be the leading segment among Dermatology, Musculoskeletal, Immunology & Inflammation, Oncology, Cardiovascular, Ophthalmology and Other Therapeutic Categories. It is predicted to grow at a CAGR of 13.1% during the period between 2022 and 2032, while its historical CAGR stands at just 11.4%. The Oncology segments grows owing to the rising cancer patients globally, government aided cancer research, Cell therapies developmentand initiatives to reduce cancer burden.

Key Takeaways from the Market Study

The developing countries are predicted to be a potential marketwith rising rates of chronic diseases, hereditary diseases, rising geriatricpopulation and higher demanding regionsfor organs and biomaterials. However,withlow awareness of Cell Regeneration Medicine and high cost of therapies, these potential markets are difficult to capture, comments a Future Market Insights analyst.

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Competitive Landscape

The Cell Regeneration MedicineMarket is driven by the Market players who are expanding their product portfolios by highly investing in the R&D and Product development areas. Government aids, technological developments, regulatory approvals, mergers and acquisitions, market expansion and a diversified product offering have all helped to maintaintheenvironment competitive.

Some of the prominent companies in the global Cell Regeneration Medicine market are AstraZeneca plc, Astellas Pharma, Inc., F. Hoffmann-La Roche Ltd., Integra Lifesciences Corp., Cook Biotech, Inc., Bayer AG, Pfizer, Inc., Merck KGaA, Abbott, Vericel Corp., Novartis AG, GlaxoSmithKline (GSK), Baxter International, Inc., Takara Bio, Inc., etc.

The key developments in the Cell Regeneration Medicine Market are:

More Insights Available

Future Market Insights, in its new offering, presents an unbiased analysis of the Cell Regeneration Medicine market, presenting historical market data (2017-2021) and forecast statistics for the period of 2022-2032.

The study reveals essential insights on the basis of Product Type (Therapeutics, Tools, Banks and Services), Therapeutic category (Dermatology, Musculoskeletal, Immunology & Inflammation, Oncology, Cardiovascular, Ophthalmology and Other Therapeutic Categories) across five regions (North America, Latin America, Europe, Asia Pacific and Middle East & Africa).

Market Segments Covered in Cell Regeneration Medicine Market Analysis

By Product Type:

By Therapeutic Category:

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Table of Content

1.1. Global Market Outlook

1.2. Demand-side Trends

1.3. Supply-side Trends

1.4. Technology Roadmap Analysis

1.5. Analysis and Recommendations

2.1. Market Coverage / Taxonomy

2.2. Market Definition / Scope / Limitations

3.1. Market Dynamics

3.1.1. Drivers

3.1.2. Restraints

3.1.3. Opportunity

3.1.4. Trends

3.2. Scenario Forecast

3.2.1. Demand in Optimistic Scenario

3.2.2. Demand in Likely Scenario

3.2.3. Demand in Conservative Scenario

3.3. Opportunity Map Analysis

3.4. Investment Feasibility Matrix

3.5. PESTLE and Porters Analysis

3.6. Regulatory Landscape

3.6.1. By Key Regions

3.6.2. By Key Countries

4.1. Historical Market Size Value (US$ Mn) Analysis, 2017-2021

4.2. Current and Future Market Size Value (US$ Mn) Projections, 2022-2032

4.2.1. Y-o-Y Growth Trend Analysis

4.2.2. Absolute $ Opportunity Analysis

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Cell Regeneration Medicine Market Analysis by Type, Application, Growth, Demand, Status, and Forecast from 2022 to 2032 - Digital Journal

Children with sickle cell disease (SCD) exposed to higher doses of the oral therapy hydroxyurea report better blood-related clinical parameters than those with lower exposure, according to a new study from the U.S.

The favorable outcomes were linked to higher adherence to treatment, suggesting that adherence interventions have the potential to improve a range of clinical outcomes, researchers wrote.

The study, Impact of hydroxyurea dose and adherence on hematologic outcomes for children with sickle cell anemia, was published inPediatric Blood & Cancer.

Hydroxyurea is a treatment that increases the levels of fetal hemoglobin a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart.

The medication has been approved in the U.S. for SCD since the late 1990s, and remains the primary disease-modifying therapy in people with the condition.

Numerous studies have demonstrated that hydroxyurea treatment can lessen the risk of hospitalization, death, and complications such as vaso-occlusive crisis. Though the efficacy of hydroxyurea in SCD is well-established, the optimal dosing strategy in a real-world setting is less clear.

Recent research done in sub-Saharan Africa suggested that clinical outcomes are better among SCD children given a high dose of hydroxyurea (mean of 29.5 mg/kg per day) compared to those who got less than 20 mg/kg/day.

Now, a team of U.S. researchers conducted an analysis to see whether the same trend would be found in children with SCD treated in the U.S.

The objective of the study was to evaluate the relationship of hydroxyurea exposure, as assessed by prescribed dose of hydroxyurea and adherence, to hematological [blood-related] parameters in children with SCD in the United States, the researchers wrote.

Adherence refers to whether patients are taking medications as directed. The researchers stressed that they were looking at how much medicine patients were actually taking not just what was prescribed as a strength of their analysis.

This study used reliable and validated adherence measures as well as EMR [electronic medical record] documented prescribing data to describe actual hydroxyurea exposure, the researchers wrote.

Compared to most previously published studies that only report the prescribed dose of hydroxyurea, this analysis incorporated hydroxyurea adherence to better describe actual hydroxyurea exposure, they added.

The scientists used data from two prior clinical trials (NCT02578017 and NCT04675645), both of which had tested interventions designed to improve adherence among children with SCD on hydroxyurea.

The data covered 45 children and young adults; just over half were male, the median age was 12 years (range 219 years), and 97.8% were Black.

The patients were divided into two groups based on their exposure to hydroxyurea. A total of 22 children took on average 20 mg/kg of the medication per day and were included in the lower exposure group. The remaining 23 patients, who took more than 20 mg/kg per day, were in the higher exposure group.

The majority of patients used hydroxyurea for more than one year (71.1%) before enrolling in the study. The remaining had been using it for longer than six months. There was no significant difference in duration of hydroxyurea treatment between the two groups.

Results showed that average levels of fetal hemoglobin were significantly elevated in the higher exposure group compared to the lower exposure group (28.9% vs. 23.4%). The team noted, however, that levels were relatively high in both exposure groups, and that there was substantial variation within each group.

Mean corpuscular volume, a measure of the size of red blood cells, also was significantly higher in the higher exposure group (average of 101 vs. 93.7 femtoliters).

These favorable outcomes resulted from both higher adherence, as represented by the higher number of days of confirmed hydroxyurea exposure, and a higher prescribed hydroxyurea dose, the researchers wrote.

The team said that these results support the need to improve adherence and optimize dosing regimens for hydroxyurea, which could be explored in future research.

Larger studies are now required to determine if increasing hydroxyurea exposure via interventions focused on optimal adherence and prescribing dosages could improve clinical outcomes in children with SCD.

Link:
Higher Hydroxyurea Exposure Tied to Better Blood Parameters in US... - Sickle Cell Anemia News

The Government's being urged to get a move on and approve a stem-cell treatment for people with multiple sclerosis (MS).

A petition was presented to Parliament on Tuesday, calling for the Health Minister to fund the treatment which has shown to halt some of the debilitating symptoms of the disease.

Three years ago Anne Besley never thought she'd be standing outside Parliament with her mum. She was in constant pain and could barely walk.

"I'm not on drugs anymore, I'm able to work part-time. I hardly ever need the crutches and there are days when I have to think hard about do I actually have MS," Besley said.

"It's all thanks to a self-funded trip to India in 2019 for expensive stem-cell treatment."

It was treatment that allowed Besley to get her life back.

That same year Wellingtonian Karyn Bishop spent more than $120,000 getting the same treatment in Russia.

She couldn't walk unaided before she left, but a year later she managed a kilometre walk around a park.

"There's so many people that miss out on it because they simply can't afford it. We're spending thousands on drugs that only work for a certain percentage of people and this treatment has been shown to work."

The treatment works by harvesting stem cells from the patient's bone marrow.

Chemotherapy is given to shut down the faulty immune system before the stem cells are put back in to grow a new immune system.

But at present it's only available for blood cancer patients.

On Tuesday the ACT Party accepted a petition with 10,000 signatures urging the Government to extend the treatment to MS.

"I would like to see more forward planning in New Zealand about the newer medicines that we are falling behind the rest of the world on," said ACT's deputy leader Brooke van Velden.

Green Party MP Golriz Ghahraman, who has MS, said it's a no-brainer.

"It is concerning to me that people are having to buy this medicine, essential medicine, on the free market. We have a healthcare system."

Health Minister Andrew Little acknowledged the treatment shows positive results but said it is up to the drug-buying agency Pharmac to decide what drugs are funded.

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Kiwis with multiple sclerosis patients thriving from overseas stem-cell treatment urge Government to approve it here - Newshub

The Medicines and Healthcare products Regulatory Agency (MHRA) has granted Global Blood Therapeutics (GBT) a British marketing authorisation for Oxbryta also known as voxelotor for both adult and paediatric patients 12 years of age and older requiring treatment of haemolytic anaemia due to sickle cell disease (SCD).

The authorisation supports the use of Oxbryta as either a monotherapy or for use in combination with hydroxycarbamide, also known as hydroxyurea.

Oxbryta is an oral treatment taken once daily and is the first medicine authorised in Britain that directly blocks sickle haemoglobin (HbS) polymerisation, which is the molecular foundation of sickling and the destruction of red blood cells in SCD.

In the UK, approximately 15,000 people are affected by SCD, a progressive and complex condition which can cause serious complications, including organ damage. For those living with the condition, it is common to experience economic disadvantages and health inequalities as SCD can inflict negative societal impacts in areas like healthcare, education and employment.

Beginning in early childhood, SCD complications can include neurocognitive impairment, acute chest syndrome and silent and overt stroke. It has been shown that early intervention and treatment of SCD can potentially change the course of this disease and, in turn, reduce symptoms and events while preventing long-term organ damage and extending life expectancy.

The marketing authorisation from the MHRA follows the European Commission (EC) authorisation which was made earlier this year and is based on data taken from the phase 3 HOPE trial. The results demonstrated clinically meaningful and statistically significant improvements in haemoglobin (Hb) levels, accompanied by a reduction of haemolysis markers, for patients treated with Oxbryta.

In 2021, Oxbryta was the first SCD treatment to be granted a Promising Innovative Medicine (PIM) designation from the MHRA, which then allowed the medicine to receive a positive scientific opinion under the Early Access to Medicines Scheme (EAMS). Healthcare professionals were then able to treat selected patients with Oxbryta ahead of market authorisation, based on clinical factors to address a clear unmet medical need.

Dr Beatriz Pujol, vice president, head of medical affairs EU & GCC at GBT, said: Following this marketing authorisation by the MHRA, we look forward to working with the National Institute of Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) with the goal of helping to facilitate rapid access to voxelotor for people living with sickle cell disease who may benefit from this important treatment.

Link:
MHRA grants marketing authorisation to Global Blood Therapeutics for sickle cell disease drug - PMLiVE

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr Stephan Grupp

Grupp, a pioneer in cellular immunotherapy at Children's Hospital of Philadelphia (CHOP), had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

"The trial opened at the absolute last possible moment that it could have been helpful to her," he told Medscape Medical News. "There was nothing else to do to temporize her further.... It had to open then or never."

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Grupp says that he is, at last, starting to use the "cure" word.

"I'm not just a doctor, I'm a scientist and one case isn't enough to have confidence about anything," he said. "We wanted more patients to be out longer to be able to say that thing which we have for a long time called the 'c word.'

"CAR T-cell therapy has now been given to hundreds of patients at CHOP, and we are unique in this we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me," he commented.

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There wasaprecedent, however. After having been "stuck" for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Grupp's colleague Carl June and his team at the University of Pennsylvania. By tweaking two key steps in the genetic modification of T cells, June's team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Grupp recalls that he was candidwith Emily's parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalls saying: "This is something outside the box, this is going to give her a chance."

Grupp, who describes himself as being "on the cowboy end" of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.

CAR T-cell therapy involves harvesting a patient's T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells "were very powerful in the short term but had almost no proliferative capacity" once they were infused back into the patient, Grupp explained.

"It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia," he said.

June's team came up with what Grupp calls "the magic formula": a bead-based manufacturing process that produced younger T-cell phenotypes with "enormous" proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

"Was it rogue? Absolutely, positively not," said Grupp, thinking back to the day he enrolled Emily in the trial. "Was it risky? Obviously...we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn't know nearly enough about the risks."

The gravest risk that Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as "tumor lysis syndrome" (N Engl J Med. 2011;365:725-33).

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome (CRS).

"The wheels just came off then," said Tom. "I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

"I remember the third or fourth night, a doctor took me in the hallway and said, 'There's a one-in-a-thousand chance your daughter is alive when the sun comes up,' " Tom told Medscape Medical News. "And I said, 'Alright, I'll see you at rounds tomorrow, because she'll still be here.' "

"We had some vague notion of toxicity...but it turned out not nearly enough," said Grupp. The ICU "worked flat out" to save her life, he recalls. "They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out."

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. "Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick," he recalls. "Could we get the result fast enough? The lab dropped everything to run the test."

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines "were just unbelievably elevated," he said. Among them was interleukin-6 (IL-6).

"IL-6 isn't even made by T cells, so nobody in the world would have guessed that this would have mattered. If we'd ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for tocilizumab so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

"So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o'clock to giving the drug to her at 8:00 o'clock, and then her clinical situation turned around so quickly I mean hours later."

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. "The doctors said, 'We've never seen anyone this sick get better any faster,' " said Tom.

She had already been through a battery of treatments for her leukemia. "It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free," he added.

Now that Emily, 17, has remained in remission for 10 years, Grupp is finally willing to use the word "cure" but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents' and patients' expectations realistic about what they see as a miracle cure.

"It's not a miracle. We can get patients into remission 90-plus percent of the time but some patients do relapse and then there are the risks [of the cytokine storm, which can be life-threatening].

"Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily...because now we're giving the tocilizumab much earlier," Grupp said.

Since their daughter's recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily's life. Tom testified at the US Food and Drug Administration's advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As co-founders of the Emily Whitehead Foundation, Tom and Karis have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to "move this revolution forward."

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Tom drew comfort from two visions, which he calls "whispers," that guided them through several forks in the road and through tough decisions about Emily's treatment.

Several times he and Kari refused treatment that was offered to Emily, and once they had her discharged against medical advice. "I told Kari she's definitely going to beat her cancer I saw it. I don't know how it's going to happen, but we're going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don't want to hear anything about 'a sign,' or what guided us, but I don't think you have to separate faith and science, I think it takes everything to make something like this to happen."

The key to the CAR T-cell breakthrough that gave rise to Emily's therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

"The fundamental question is, are the cells still working, or are the patients cured and they don't need them?" said Grupp. "I think it's the latter. The data that we have from several large datasets that we developed with Novartis are that if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point."

While it's still not clear if and when that risk will ever get to zero, Emily and Grupp have successfully closed the chapter.

"Oncologists have different notions of what the word 'cure' means. If your attitude is you're not cured until you've basically reached the end of your life and you haven't relapsed, well, that's an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that's what a functional cure looks like," he said.

"I'm probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it's about making sure there's no long-term side effects from the totality of her treatment. Generally, for a patient who's gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it."

Tom, Emily, and Kate Whitehead

As for the Whiteheads, they are focused on Emily's college applications, her new driver's license, and her project to co-write a film about her story with a Hollywood filmmaker.

Tom says the one thing he hopes clinicians take away from their story is that sometimes a parent's instinct transcends science.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

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CAR T-Cell Therapy Turns 10 and Finally Earns the Word 'Cure' - Medscape

Kira MacDougall, MD, and Muhammad Rafay Khan Niazi, MD, spoke with CancerNetwork about their research into the significance of peripheral blood biomarkers of response to immunotherapy in nonsmall cell lung cancer published in the journal ONCOLOGY.

Kira MacDougall, MD, a first year fellow at the University of Oklahoma, and Muhammad Rafay Khan Niazi, MD, a third year resident of Internal Medicine at Staten Island University Hospital, spoke with CancerNetwork about research published in the journal ONCOLOGY titled, The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated With Pembrolizumab: A Clinical Study.

MacDougall and Niazi discuss the clinical utility of absolute lymphocyte count (ALC) and the ratio of absolute neutrophil count to ALC for predicting outcomes with pembrolizumab (Keytruda) in advanced nonsmall cell lung cancer. They also talked about future research in the space and what unanswered questions remain in this treatment setting.

Dont forget to subscribe to the Oncology Peer Review On-The-Go podcast on Apple Podcasts, Spotify, or anywhere podcasts are available.

See the original post here:
Oncology Peer Review On-The-Go: The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated...

image:Chromosome segregation In dividing cells. Cell cytoskeleton is depicted in red, DNA is depicted in blue and a protein that marks dividing cells is depicted in green. view more

Credit: Tom Winkler, Ben David lab.

The researchers caution: "The CRISPR genome editing method is very effective, but not always safe. Sometimes cleaved chromosomes do not recover and genomic stability is compromised which in the long run might promote cancer."

A new study from TAU identifies risks in the use of CRISPR therapeutics an innovative, Nobel-prize-winning method that involves cleaving and editing DNA, already employed for the treatment of conditions like cancer, liver and intestinal diseases, and genetic syndromes. Investigating the impact of this technology on T-cells white blood cells of the immune system, the researchers detected a loss of genetic material in a significant percentage up to 10% of the treated cells. They explain that such loss can lead to destabilization of the genome, which might cause cancer.

The study was led by Dr. Adi Barzel from the School of Neurobiology, Biochemistry and Biophysics at TAU's Wise Faculty of Life Sciences and Dotan Center for Advanced Therapies, a collaboration between the Tel Aviv Sourasky Medical Center (Ichilov) and Tel Aviv University, and by Dr. Asaf Madi and Dr. Uri Ben-David from TAU's Faculty of Medicine and Edmond J. Safra Center for Bioinformatics. The findings were published in the leading scientific journal Nature Biotechnology.

The researchers explain that CRISPR is a groundbreaking technology for editing DNA cleaving DNA sequences at certain locations in order to delete unwanted segments, or alternately repair or insert beneficial segments. Developed about a decade ago, the technology has already proved impressively effective in treating a range of diseases cancer, liver diseases, genetic syndromes, and more. The first approved clinical trial ever to use CRISPR, was conducted in 2020 at the University of Pennsylvania, when researchers applied the method to T-cells white blood cells of the immune system. Taking T-cells from a donor, they expressed an engineered receptor targeting cancer cells, while using CRISPR to destroy genes coding for the original receptor which otherwise might have caused the T-cells to attack cells in the recipient's body.

In the present study, the researchers sought to examine whether the potential benefits of CRISPR therapeutics might be offset by risks resulting from the cleavage itself, assuming that broken DNA is not always able to recover.

Dr. Ben-David and his research associate Eli Reuveni explain: "The genome in our cells often breaks due to natural causes, but usually it is able to repair itself, with no harm done. Still, sometimes a certain chromosome is unable to bounce back, and large sections, or even the entire chromosome, are lost. Such chromosomal disruptions can destabilize the genome, and we often see this in cancer cells. Thus, CRISPR therapeutics, in which DNA is cleaved intentionally as a means for treating cancer, might, in extreme scenarios, actually promote malignancies."

To examine the extent of potential damage, the researchers repeated the 2020 Pennsylvania experiment, cleaving the T-cells' genome in exactly the same locations chromosomes 2, 7, and 14 (of the human genome's 23 pairs of chromosomes). Using a state-of-the-art technology called single-cell RNA sequencing they analyzed each cell separately and measured the expression levels of each chromosome in every cell.

In this way, a significant loss of genetic material was detected in some of the cells. For example, when Chromosome 14 had been cleaved, about 5% of the cells showed little or no expression of this chromosome. When all chromosomes were cleaved simultaneously, the damage increased, with 9%, 10%, and 3% of the cells unable to repair the break in chromosomes 14, 7, and 2 respectively. The three chromosomes did differ, however, in the extent of the damage they sustained.

Dr. Madi and his student Ella Goldschmidt explain: "Single-cell RNA sequencing and computational analyses enabled us to obtain very precise results. We found that the cause for the difference in damage was the exact place of the cleaving on each of the three chromosomes. Altogether, our findings indicate that over 9% of the T-cells genetically edited with the CRISPR technique had lost a significant amount of genetic material. Such loss can lead to destabilization of the genome, which might promote cancer."

Based on their findings, the researchers caution that extra care should be taken when using CRISPR therapeutics. They also propose alternative, less risky, methods, for specific medical procedures, and recommend further research into two kinds of potential solutions: reducing the production of damaged cells or identifying damaged cells and removing them before the material is administered to the patient.

Dr. Barzel and his PhD student Alessio Nahmad conclude: "Our intention in this study was to shed light on potential risks in the use of CRISPR therapeutics. We did this even though we are aware of the technology's substantial advantages. In fact, in other studies we have developed CRISPR-based treatments, including a promising therapy for AIDS. We have even established two companies one using CRISPR and the other deliberately avoiding this technology. In other words, we advance this highly effective technology, while at the same time cautioning against its potential dangers. This may seem like a contradiction, but as scientists we are quite proud of our approach, because we believe that this is the very essence of science: we don't 'choose sides.' We examine all aspects of an issue, both positive and negative, and look for answers."

Link to the article:

https://www.nature.com/articles/s41587-022-01377-0

Nature Biotechnology

Frequent aneuploidy in primary human T cells after CRISPRCas9 cleavage

30-Jun-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

See the article here:
CRISPR therapeutics can damage the genome - EurekAlert

image:Drug B binds to the surface of the cell and is transported to the Golgi apparatus. The drug contains an endoplasmic reticulum (ER)-specific sequence to further guide its transport to the ER. Transport to the ER is stopped if the drug bears N-glycosylation Y. view more

Credit: Ayano Satoh from Okayama University

Proteins usually undergo modifications during or after their synthesis in the endoplasmic reticulum (ER) and Golgi apparatus network inside eukaryotic cells. One such modification is glycosylation, whereby sugars, such as glycans, are added to newly synthesized proteins. Glycans allow proteins to fold properly, in turn making them stable and biologically active for various cell processes. However, the exact mechanism of glycosylation in the ER and Golgi are still not known. One way to study the process of glycosylation during protein synthesis is to deliver synthetic proteins to specific cell organelles and observe their subcellular dynamics. But this is often hindered by the lack of specific delivery methods to organelles like the ER and Golgi.

To this end, Dr. Ayano Satoh from Okayama University and Dr. Yuta Maki, Kazuki Kawata, Dr. Yanbo Liu, Kang-Ying Goo, Dr. Ryo Okamoto, and Prof.Dr. Yasuhiro Kajihara from Osaka University, Japan investigated the feasibility of modifying cholera toxin (CT) for targeted delivery to the ER and Golgi. CT is a protein produced by the bacterium Vibrio cholerae and is responsible for the hallmark symptoms of diarrhearepeated loose, watery stools. The toxin is made up of two subunits: CTA, which causes diarrhea, and CTB, which helps the toxin enter cells. CT enters the cell through the membrane into small cellular vehicles called endosomes that deliver it to the Golgi bodies. From there, an ER-specific amino acid sequence of CTA takes CT into the ER, where the toxin springs into action to cause diarrhea. CT is a protein that naturally gets delivered specifically to the Golgi and ER. This made it an attractive candidate for our investigation, says Dr. Satoh, explaining the reason behind selecting this protein for their study, which was first published on May 23, 2022, in Chemistry A European Journal.

The team synthesized an artificial, glycosylated form of the non-toxic CTB and tracked its intracellular journey using the HiBiT bioluminescence system engineered from the luciferase enzyme. In the system that the team used, the larger fragment of luciferase was added to particular receptors on the ER and Golgi. CTB was tagged with the smaller fragment of luciferase. The system works by emitting light when the two fragments bind to each other. Thus, the team tracked the artificial CTBs movement through the organelles in real time by checking for the emittance of light. Talking about the highlights of their study, Dr. Satoh says, We designed and chemically synthesized the glycosyl-CTB and demonstrated its trafficking into the ER and Golgi of living cells. We also established a method to quantitatively monitor the trafficking of CTB to these organelles.

The successful monitoring and delivery of the artificial CTB may pave the way for a new phase of research in understanding protein modification in compartments of living cells. The team emphasizes that their method of preparing CTB allows for developing various mutant forms of the protein as well as CTB bearing different glycans on its surface to help investigate the functions of N-glycan in cells.

Not only the study of glycans but CTB-mediated delivery can also be a promising tool for target-specific drug delivery in cells and organelles. Dr. Satoh observes, Our system for targeting specific organelles may help treat diseases caused by the absence of enzymes localized in specific organelles.

What is her vision for the future? Current drug delivery techniques are limited because they only target the cell surface. Our system may extend the limits of current technology and enable the delivery of drug wherever it is needed, says a hopeful Dr. Satoh.

We have our fingers crossed for her vision to come true and revolutionize the field of medicine!

About Okayama University, Japan

As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.

Website: https://www.okayama-u.ac.jp/index_e.html

About Professor Ayano Satoh from Okayama University, Japan

Dr. Ayano Satoh is an Associate Professor of the Graduate School of Interdisciplinary Science and Engineering in Health Systems and the Faculty of Engineering at the Okayama University, Okayama, Japan. She obtained her Bachelors and Masters degrees in Chemistry from Ochanomizu University, Tokyo, Japan. She then received her PhD at the Graduate School of Humanities and Sciences, Ochanomizu University, where she worked on affinity interactions among lipids, glycans, and proteins with Dr. Isamu Matsumoto. Before joining Okayama University, she worked with Dr. Graham Warren at Yale University, first as a Postdoctoral Researcher, and then as a Research Scientist. At Yale University, she worked on transport within the Golgi apparatus.

Chemistry - A European Journal

Experimental study

Cells

Design and Synthesis of Glycosylated Cholera Toxin B Subunit as a Tracer of Glycoprotein Trafficking in Organelles of Living Cells

23-May-2022

The authors declare no conflict of interest.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

The rest is here:
To cell surface and beyond: Tracing subcellular glycoprotein transport using modified cholera toxin - EurekAlert