Category Archives: Genetic Medicine

In March 2022, Sentynl acquired the global rights to NULIBRY and is responsible for the ongoing development and commercialization of NULIBRY in the United States and developing, manufacturing, and commercializing fosdenopterin globally. Sentynl and BridgeBio share development responsibilities through the approval of the marketing authorization application under accelerated assessment with the EMA and through approval of NULIBRY's regulatory submission with the Israeli Ministry of Health.

"Our work on NULIBRY and MoCD Type A epitomizes BridgeBio's belief that no disease is too rare to address. With this positive CHMP opinion, we are closer to delivering a treatment option to all children across the globe who suffer with MoCD Type A," said BridgeBio founder and CEO Neil Kumar, Ph.D.

The positive CHMP opinion is supported by data from three clinical trials that demonstrated efficacy of NULIBRY for the treatment of patients with MoCD Type A compared to data from a natural history study. These studies showed that NULIBRY reduced the risk of death by 86% and increased the probability of survival to 86% at three years compared to 52% in the untreated, genotype-matched, historical control group in the natural history study.

"We are thrilled by the CHMP's recommendation in favor of NULIBRY and hope that patients living with MoCD Type A in Europe and around the world can access this therapy," said Matt Heck, CEO of Sentynl. "The CHMP positive opinion marks important progress not only for the program but also for the MoCD Type A patients outside of the U.S. who are seeking ways to treat their life-threatening and progressive disease."

Based on the CHMP recommendation, a decision by the EC, which authorizes marketing applications in the EU, is expected on the NULIBRY application later this year. The recommendation for marketing authorization under exceptional circumstances is granted to medicines where the applicant is unable to provide comprehensive data under normal conditions of use because the disease being treated is so rare.

In April 2022, BridgeBio received New Drug Application (NDA) Approval in Principle from the Israeli Ministry of Health and the application is currently undergoing the final review processes.

About Molybdenum Cofactor Deficiency (MoCD) Type AMoCD Type A is an autosomal recessive, inborn error of metabolism caused by mutations in the molybdenum cofactor synthesis 1 gene and characterized by a deficiency in molybdenum cofactor production, leading to a lack of molybdenum-dependent enzyme activity.1,2 The lack of activity leads to decreased sulfite oxidase activity with buildup of sulfite and secondary metabolites (such as S-sulfocysteine) in the brain, which causes irreversible neurological damage.2

MoCD Type A is an ultra-rare disease. The incidence and prevalence of MoCD Type A in the European Union are not known, but the estimated prevalence is 0.005 per 10,000 persons. Based on these estimates, MoCD Type A is likely to be underdiagnosed.

The most common presenting symptoms of MoCD Type A are seizures, feeding difficulties and encephalopathy. Patients with MoCD Type A who survive beyond infancy typically suffer from progressive brain damage, which presents in characteristic patterns on magnetic resonance imaging (MRI). This damage leads to severe psychomotor impairment and an inability to make coordinated movements or communicate with their environment.

About NULIBRY(Fosdenopterin) for Injection

NULIBRY(Fosdenopterin) for Injection is a substrate replacement therapy that provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase, an enzyme that reduces levels of neurotoxic sulfites. It is the first and only FDA-approved therapy indicated to reduce the risk of mortality in patients with MoCD Type A, and clinical trials have demonstrated that patients treated with NULIBRY or rcPMP had an improvement in overall survival compared to the untreated, genotype-matched, historical control group.

References1 Mechler K et al. Genet Med. 2015;17(12):965-970.2 Schwarz G. Cur Op in Che Bio. 2016;31:179-187.

About BridgeBio Pharma, Inc.BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers. BridgeBio's pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visitbridgebio.comand follow us onLinkedInandTwitter.

About Sentynl TherapeuticsSentynl Therapeutics is a U.S.-based biopharmaceutical company focused on bringing innovative therapies to patients living with rare diseases. The company was acquired by the Zydus Group in 2017. Sentynl's experienced management team has previously built multiple successful pharmaceutical companies. With a focus on commercialization, Sentynl looks to source effective and highly differentiated products across a broad spectrum of therapeutic areas to address unmet needs. Sentynl is committed to the highest ethical standards and compliance with all applicable laws, regulations, and industry guidelines. For more information, visitwww.sentynl.com.

About ZydusThe Zydus Group, with an overarching purpose of empowering people with freedom to live healthier and more fulfilled lives, is an innovative, global pharmaceutical company that discovers, develops, manufactures, and markets a broad range of healthcare therapies. The group employs over 23000 people worldwide and is driven by its mission to unlock new possibilities in life-sciences through quality healthcare solutions that impact lives. The group aspires to become a global life-sciences company transforming lives through pathbreaking discoveries. For more information, visithttps://www.zyduslife.com/zyduslife/.

BridgeBio Pharma, Inc. Forward-Looking StatementsThis press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the "Securities Act"), and Section 21E of the Securities Exchange Act of 1934, as amended (the "Exchange Act"), which are usually identified by the use of words such as "anticipates," "believes," "estimates," "expects," "intends," "may," "plans," "projects," "seeks," "should," "will," and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to, the timing and outcome of the EC's decision on NULIBRY, the potential ability for NULIBRY to be the first and only approved therapy in the EU to treat patients with MoCD type A, and the potential ability to provide treatment options to MoCD Type A patients in Europe and around the world, reflect our current views about our plans, intentions, expectations, strategies and prospects, and are based on the information currently available to us and on assumptions we have made and are not forecasts, promises nor guarantees. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by these forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, the success of our ongoing collaboration with Sentynl, including our co-development responsibilities through approval of the marketing authorization application under accelerated assessment with the EMA and through approval of NULIBRY's regulatory submission with the Israeli Ministry of Health, Sentynl's ability to successfully develop and commercialize NULIBRY in the United States and to develop, manufacture, and commercialize fosdenopterin globally, , as well as those risks set forth in the Risk Factors section of our most recent Annual Report on Form 10-K and BridgeBio Pharma's other SEC filings. Moreover, we operate in a very competitive and rapidly changing environment in which new risks emerge from time to time. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

BridgeBio Contact:Grace Rauh[emailprotected](917) 232-5478

Sentynl Therapeutics Contact:Michael Hercz[emailprotected](888) 507-5296

SOURCE Sentynl Therapeutics

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BridgeBio Pharma and Sentynl Therapeutics Receive Positive CHMP Opinion for NULIBRY (fosdenopterin) for the Treatment of MoCD Type A - PR Newswire

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.

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CRISPR therapeutics can damage the genome - EurekAlert

Last Christmas, as the Omicron variant was ricocheting around the United States, Mary Carrington unknowingly found herself at a superspreader eventan indoor party, packed with more than 20 people, at least one of whom ended up transmitting the virus to most of the gatherings guests.

After two years of avoiding the coronavirus, Carrington felt sure that her time had come: Shed been holding her great-niece, who tested positive soon after, and she was giving me kisses, Carrington told me. But she never caught the bug. And I just thought, Wow, I might really be resistant here. She wasnt thinking about immunity, which she had thanks to multiple doses of a COVID vaccine. Rather, perhaps via some inborn genetic quirk, her cells had found a way to naturally repel the pathogens assaults instead.

Carrington, of all people, understood what that would mean. An expert in immunogenetics at the National Cancer Institute, she was one of several scientists who, beginning in the 1990s, helped uncover a mutation that makes it impossible for most strains of HIV to enter human cells, rendering certain people essentially impervious to the pathogens effects. Maybe something analogous could be safeguarding some rare individuals from SARS-CoV-2 as well.

Read: America is running out of COVID virgins

The idea of coronaviral resistance is beguiling enough that scientists around the world are now scouring peoples genomes for any hint that it exists. If it does, they could use that knowledge to understand whom the virus most affects, or leverage it to develop better COVID-taming drugs. For individuals who have yet to catch the contagiona fast-dwindling proportion of the populationresistance dangles like a superpower that people cant help but think they must have, says Paula Cannon, a geneticist and virologist at the University of Southern California.

As with any superpower, though, bona fide resistance to SARS-CoV-2 infection would likely be very rare, says Helen Su, an immunologist at the National Institutes of Allergy and Infectious Disease. Carringtons original hunch, for one, eventually proved wrong: She recently returned from a trip to Switzerland and found herself entwined with the virus at last. Like most people who remained unscathed until recently, Carrington had done so for two and a half years through a probable combination of vaccination, cautious behavior, socioeconomic privilege, and luck. Its entirely possible that inborn coronavirus resistance may not even existor that it may come with such enormous costs that its not worth the protection it theoretically affords.

Of the 1,400 or so viruses, bacteria, parasites, and fungi known to cause disease in humans, Jean-Laurent Casanova, a geneticist and an immunologist at Rockefeller University, is certain of only three that can be shut out by bodies with one-off genetic tweaks: HIV, norovirus, and a malaria parasite.

The HIV-blocking mutation is maybe the most famous. About three decades ago, researchers, Carrington among them, began looking into a small number of people who we felt almost certainly had been exposed to the virus multiple times, and almost certainly should have been infected, and yet had not, she told me. Their superpower was simple: They lacked functional copies of a gene called CCR5, which builds a cell-surface protein that HIV needs in order to hack its way into T cells, the viruss preferred human prey. Just 1 percent of people of European descent harbor this mutation, called CCR5-32, in two copies; in other populations, the trait is rarer still. Even so, researchers have leveraged its discovery to cook up a powerful class of antiretroviral drugs, and purged the virus from two people with the help of 32-based bone-marrow transplantsthe closest that medicine has come to developing a functional HIV cure.

The stories with those two other pathogens are similar. Genetic errors in a gene called FUT2, which pastes sugars onto the outsides of gut cells, can render people resistant to norovirus; a genomic tweak erases a protein called Duffy from the walls of red blood cells, stopping Plasmodium vivax, one of several parasites that causes malaria, from wresting its way inside. The Duffy mutation, which affects a gene called DARC/ACKR1, is so common in parts of sub-Saharan Africa that those regions have driven rates of P. vivax infection way down.

In recent years, as genetic technologies have advanced, researchers have begun to investigate a handful of other infection-resistance mutations against other pathogens, among them hepatitis B virus and rotavirus. But the links are tough to definitively nail down, thanks to the number of people these sorts of studies must enroll, and to the thorniness of defining and detecting infection at all; the case with SARS-CoV-2 will likely be the same. For months, Casanova and a global team of collaborators have been in contact with thousands of people from around the world who believe they harbor resistance to the coronavirus in their genes. The best candidates have had intense exposures to the virussay, via a symptomatic person in their homeand continuously tested negative for both the pathogen and immune responses to it. But respiratory transmission is often muddied by pure chance; the coronavirus can infiltrate people silently, and doesnt always leave antibodies behind. (The team will be testing for less fickle T-cell responses as well.) People without clear-cut symptoms may not test at all, or may not test properly. And all on its own, the immune system can guard people against infection, especially in the period shortly after vaccination or illness. With HIV, a virus that causes chronic infections, lacks a vaccine, and spreads through clear-cut routes in concentrated social networks, it was easier to identify those individuals whom the virus had visited but not put down permanent roots within, says Ravindra Gupta, a virologist at the University of Cambridge. SARS-CoV-2 wont afford science the same ease of study.

Read: Is BA.5 the reinfection wave?

A full analogue to the HIV, malaria, and norovirus stories may not be possible. Genuine resistance can manifest in only so many ways, and tends to be born out of mutations that block a pathogens ability to force its way into a cell, or xerox itself once its inside. CCR5, Duffy, and the sugars dropped by FUT2, for instance, all act as microbial landing pads; mutations rob the bugs of those perches. If an equivalent mutation exists to counteract SARS-CoV-2, it might logically be found in, say, ACE2, the receptor that the coronavirus needs in order to break into cells, or TMPRSS2, a scissors-like protein that, for at least some variants, speeds the invasive process along. Already, researchers have found that certain genetic variations can dial down ACE2s presence on cells, or pump out junkier versions of TMPRSS2hints that there could be tweaks that further strip away the molecules. But ACE2 is very important to blood-pressure regulation and the maintenance of lung-tissue health, said Su, of NIAID, whos one of many scientists collaborating with Casanova to find SARS-CoV-2 resistance genes. A mutation that keeps the coronavirus out might very well muck around with other aspects of a persons physiology. That could make the genetic tweak vanishingly rare, debilitating, or even, as Gupta put it, not compatible with life. People with the CCR5-32 mutation, which halts HIV, are basically completely normal, Cannon told me, which means HIV kind of messed up in choosing CCR5. The coronavirus, by contrast, has figured out how to exploit something vital to its hostan ingenious invasive move.

The superpowers of genetic resistance can have other forms of kryptonite. A few strains of HIV have figured out a way to skirt around CCR5, and glom on to another molecule, called CXCR4; against this version of the virus, even people with the 32 mutation are not safe. A similar situation has arisen with Plasmodium vivax, which we do see in some Duffy-negative individuals, suggesting that the parasite has found a back door, says Dyann Wirth, a malaria researcher at Harvards School of Public Health. Evolution is a powerful strategyand with SARS-CoV-2 spewing out variants at such a blistering clip, I wouldnt necessarily expect resistance to be a checkmate move, Cannon told me. BA.1, for instance, conjured mutations that made it less dependent on TMPRSS2 than Delta was.

Read: The BA.5 wave is what COVID normal looks like

Still, protection doesnt have to be all or nothing to be a perk. Partial genetic resistance, too, can reshape someones course of disease. With HIV, researchers have pinpointed changes in groups of so-called HLA genes that, through their impact on assassin-like T cells, can ratchet down peoples risk of progressing to AIDS. And a whole menagerie of mutations that affect red-blood-cell function can mostly keep malaria-causing parasites at baythough many of these changes come with a huge human cost, Wirth told me, saddling people with serious clotting disorders that can sometimes turn lethal themselves.

With COVID-19, too, researchers have started to home in on some trends. Casanova, at Rockefeller, is one of several scientists who has led efforts unveiling the importance of an alarm-like immune molecule called interferon in early control of infection. People who rapidly pump out gobs of the protein in the hours after infection often fare just fine against the virus. But those whose interferon responses are weak or laggy are more prone to getting seriously sick; the same goes for people whose bodies manufacture maladaptive antibodies that attack interferon as it passes messages between cells. Other factors could toggle the risk of severe disease up or down as well: cells ability to sense the virus early on; the amount of coordination between different branches of defense; the brakes the immune system puts on itself, so it does not put the hosts own tissues at risk. Casanova and his colleagues are also on the hunt for mutations that might alter peoples risk of developing long COVID and other coronaviral consequences. None of these searches will be easy. But they should be at least simpler than the one for resistance to infection, Casanova told me, because the outcomes theyre measuringserious and chronic forms of diseaseare that much more straightforward to detect.

If resistance doesnt pan out, that doesnt have to be a letdown. People dont need total blockades to triumph over microbesjust a defense thats good enough. And the protection were born with isnt all the leverage weve got. Unlike genetics, immunity can be easily built, modified, and strengthened over time, particularly with the aid of vaccines. Those DIY defenses are probably what kept Carringtons case of COVID down to a mild course, she told me. Immune protection is also a far surer bet than putting a wager on what we may or may not inherit at birth. Better to count on the protections we know we can cook up ourselves, now that the coronavirus is clearly with us for good.

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Could Genetics Be the Key to Never Getting the Coronavirus? - The Atlantic

Led by UNC School of Medicines Weili Lin, PhD, researchers documented significant decrease in neural flexibility across the entire brain of children with ADHD and throughout sub-networks considered crucial to cognitive flexibility.

CHAPEL HILL, NC Multitasking is not just an office skill. Its key to functioning as a human, and it involves something called cognitive flexibility the ability to smoothly switch between mental processes. UNC scientists conducted a study to image the neural activity analogues to cognitive flexibility and discover differences in the brain activity of children with ADHD and those without.

Their findings, in the journal Molecular Psychiatry, could help doctors diagnose children with ADHD and monitor the severity of the condition and treatment effectiveness.

Some people are more cognitively flexible than others. Its just the luck of the genetic draw in some ways, though we can improve our cognitive flexibility once we realize were being inflexible. Think of it like this: were cognitively flexible when we can start dinner, let the onions simmer, text a friend, return to making dinner without scorching the onions, and then finish dinner while also carrying on a conversation with your spouse. Were also cognitively flexible when we switch communication styles while talking to a friend and then a daughter and then a coworker, or when we solve problems creatively, say, when you realize you dont have onions to make the dinner you want, so you need a new plan.

Its part of our executive function, which includes accessing memories and exhibiting self control. Poor executive function is a hallmark of ADHD in children and adults.

When were cognitively inflexible, we cant focus on some of the tasks, we pick up the phone and scroll social media without thinking, forgetting what were doing while making dinner. In adults but especially in children, such cognitive inflexibility can wreak havoc with an individuals ability to learn and accomplish tasks.

UNC scientists led by senior author Weili Lin, PhD, director of the UNC Biomedical Research Imaging Center (BRIC), wanted to find out whats happening throughout the brain when executive function, particularly cognitive flexibility, is off line.

Lin and colleagues used functional magnetic resonance imaging (fMRI) to study the neural flexibility of 180 children diagnosed with ADHD and 180 typically developing children.

We observed significantly decreased neural flexibility in the ADHD group at both the whole brain and sub-network levels, said Lin, the Dixie Boney Soo Distinguished Professor of Neurological Medicine in the UNC Department of Radiology, particularly for the default mode network, attention-related networks, executive function-related networks, and primary networks of the brain involved in sensory, motor and visual processing.

The researchers also found that children with ADHD who received medication exhibited significantly increased neural flexibility compared to children with ADHD who were not taking medication. Children on medication displayed neural flexibility that was not statistically different from the group of traditionally developing children.

Lastly, the researchers found that they could use fMRI to discover neural flexibility differences across entire brain regions between children with ADHA and the traditionally developing children.

And we were able to predict ADHD severity using clinical measures of symptom severity, Lin said. We think our study demonstrate the potential clinical utility of neural flexibility to identify children with ADHD, as well as to monitor treatment responses and the severity of the condition in individual children.

Other authors of the paper are first author Weiyan Yin, Tengfei Li, Jessica Cohen, Hongtu Zhu, Ziliang Zhu all of UNC-Chapel Hill and Peter Mucha, formerly of UNC and now at Dartmouth University.

The National Institutes of Health, Autism Speaks, the Stavros Niarchos Foundation, the Leon Levy Foundation, and an endowment from Phyllis Green and Randolph Cowen funded this research.

Media contact: Mark Derewicz, 919-923-0959.

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Researchers Use MRI to Show Brain Changes, Differences in Children with ADHD | Newsroom - UNC Health and UNC School of Medicine

Health and medicine | News releases | Population Health | Research | Science

July 22, 2022

This image, taken by a scanning electron microscope, shows a human H9 T cell infected by HIV.National Institute of Allergy and Infectious Diseases

A study published July 19 in the journal eLife brings new hope for HIV treatments. The research by scientists at the University of Washington, the Max Planck Institute for Dynamics and Self-Organization and the University of Cologne indicates that carefully designed cocktails of broadly neutralizing antibodies, or bNAbs, could help treat HIV while minimizing the risk of the virus evolving to escape treatment.

The study shows that computational approaches to selecting combinations of bNAbs based on viral genetics could help prevent viral escape, making HIV treatment more effective.

Our study shows that leveraging genetic data can help us design more effective HIV therapies, said senior author Armita Nourmohammad, a UW assistant professor of physics. Our approach may also be useful for designing therapies against other rapidly evolving agents that cause disease, such as the Hepatitis C virus, drug-resistant bacteria or cancer tumor cells.

Antibodies are a class of proteins made by the immune system to recognize and fight pathogens. In HIV infections, bNAbs are a specific subset of antibodies that recognize multiple strains of HIV.

Broadly neutralizing antibodies offer a promising new tool to treat or potentially cure infections with rapidly evolving viruses such as HIV. But clinical trials using a single bNAb to treat HIV have shown that some viral strains may survive the treatment and lead to a rebound of viruses in the blood. Combinations of bNAbs may therefore be a more effective approach, but finding the best combinations is a challenge.

For our study, we proposed using a computational approach to predict the effectiveness of bNAb combinations based on the HIV genetics, said lead author Colin LaMont, a researcher at the Max Planck Institute for Dynamics and Self-Organization in Germany.

The team used high-throughput DNA sequencing to analyze the genomes of HIV viruses collected over 10 years from 11 untreated patients with HIV. They used these data to predict which viral strains might be able to escape treatment with different bNAbs and whether evolving to dodge bNAbs was associated with a survival cost. Next, using computational methods, they applied the knowledge gained to predict viral rebounds in three real-life trials using bNAbs. Finally, the team used their computational approach to develop a combination of bNAbs that is least likely to allow any virus to escape.

In the process, they discovered reasons why some bNAbs target broader populations of HIV than others. For example, some bNAbs, such as one called 10-1074, perform better against diverse populations of viruses because mutations that allow viruses to escape from 10-1074 also make those viruses less likely to survive. Others bNAbs, including one called PGT121, are more effective against viral populations with lower genetic diversity because mutations that enable escape are rare. Overall, the results suggested that the optimal combination includes three bNAbs: PG9, PGT151 and VRC01.

Weve shown the combination of PG9, PGT151 and VRC01 reduces the chance of viral rebound to less than 1%, said LaMont. It does this by targeting three different regions of the virus protective outer wrapping, or envelope.

Combining bNAbs, administered via intravenous infusion every few months, with current antiretroviral therapies that require daily doses could further improve long-term HIV treatment success, said Nourmohammad.

Antiretroviral therapy reduces the ability of HIV to multiply and create new variants, limiting the genetic diversity of the viral population and lowering the likelihood for emergence of bNAb escape variants. The authors say that future studies are needed to confirm the potential benefits of combining antiretroviral therapy and broadly neutralizing antibodies.

Co-authors on the study are Jakub Otwinowski at the Max Planck Institute for Dynamics and Self-Organization and Kanika Vanshylla, Henning Gruell and Florian Klein at the University of Cologne in Germany. The research was funded by the National Science Foundation, the German Research Foundation and the Max Planck Institute for Dynamics and Self-Organization.

For more information, contact Nourmohammad at armita@uw.edu.

Adapted from a press release by eLife.

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Novel HIV combination therapies could prevent viral escape and rebound - University of Washington

There is a new theory about what may be causingpuzzling casesof pediatric hepatitis of unknown origin and it is complex.

Two new and as-yet-unpublished studies from scientists in the United Kingdom theorize that children who have developed the hepatitis cases may have been co-infected with two different viruses and had a genetic predisposition to have an over-exuberant immune response when that happened.

Previously the leading hypothesis was that adenovirus 41, which had been found in a number of the infected children, was causing the liver damage. Adenovirus 41 has been known to trigger liver damage in immunocompromised children, but had never been seen to do so in children with intact immune systems.

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But the new studies report finding the presence of something called adeno-associated virus 2 AAV2 for short in the blood and in liver tissues from a number of affected children. They also found the children were infected with adenoviruses or herpes viruses.

Adeno-associated virus 2 is what is known as a dependoparvovirus. It cannot replicate in a hosts cells unless another virus is present.

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If correct, this theory does not rule out the possibility that adenovirus 41 may have played a role in the cases, said Angela Rasmussen, a virologist at the University of Saskatchewans Vaccine and Infectious Disease Organization.

It suggests that AdV 41 (or another helper virus) is necessary but not sufficient, she told STAT by email.

If this is correct, she added, you need the combination of all three a helper virus, such as adenovirus 41, the adeno-associated virus 2, and the genetic predisposition.

In fact, Judy Breuer, senior author of one of the papers, said the group very much thinks that adenovirus primarily but not exclusively adenovirus 41 is involved. We feel very certain that the adenovirus is playing a role in some way, Breuer, a clinical virologist at University College London and a consultant at Great Ormond Street Hospital for Children, told STAT in an interview.

Adeno-associated viruses are not typically looked for when clinicians are trying to figure out the cause of an illness, she said, because they havent been thought to be harmful. But her group cast a very wide net when studying samples from some of the children in the outbreak, not looking to see if a particular pathogen was present but to get a picture of all the possible disease agents their specimens contained.

She warned, though, that it is still possible that AAV2 is a bystander, not part of the cause of these hepatitis cases.

Meanwhile the second group of scientists, who are mostly from Scotland, looked at the genetic makeup of a group of affected children there. Eight of nine children studied had a particular genetic variant that affects the way the immune system responds to a threat. Nearly 16% of blood donors from Scotland have this genetic mutation. Doctors in Scotland were among the first to report on the unusual hepatitis cases in the spring.

The fact that these children had this particular immune genetic makeup we hypothesize that it made them susceptible to a new overreaction to one or both of the viruses, Breuer said.

Mario Koopmans, head of the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands, said the theory is worthy of further investigation, but at this point is not conclusive. It does suggest there is something to the combination of AAV2 and Adeno or possibly other viruses, she said in an email.

The new studies still must go through peer review. But if they are correct, they will help to explain why some medical centers that treat children with liver ailments have seen what appear to be unusual numbers of cases of unexplained hepatitis starting last fall and through the spring.

More than 1,000 such cases from 35 countries have been reported to the World Health Organization. Of that total, 22 children have died and 46 have needed liver transplants. In the United States, 355 possible cases are under investigation, the Centers for Disease Control and Prevention says. As of late June, 20 of those children had required liver transplants and 11 had died.

The studies also suggested that the disruption of normal life triggered by the pandemic may have contributed to increased transmission of adeno-associated virus 2 and adenoviruses when Covid-19 control measures started to ease, because more children would have been susceptible to them. That, in turn, would have led to an increased number of cases of hepatitis in children.

The current outbreak followed relaxation of restrictions due to the pandemic and represented one of many infections, including other enteric pathogens such as norovirus, that occurred in UK children following return to normal [social] mixing, Breuer and her co-authors wrote.

Koopmans agreed. The combination of two viruses and a genetic susceptibility factor does fit the hypothesis that the elevation in cases became visible due to the unusual occurrence of common infections, as the patterns for several endemic viruses were disturbed by the COVID 19 control measures.

Alasdair Munro, a clinical research fellow in pediatric infectious diseases at Britains University Hospital Southampton, found the papers persuasive.

Everything seems to fit, will be interesting to see if further examination can confirm this as the cause hopefully putting to bed some of the debates,he wroteon Twitter.

But Rasmussen cautioned that there are more pieces of the puzzle to be found, including how this trio of factors would cause the damage that has been seen.

I think the important things to keep in mind here are that this is correlation, not causation, she wrote. More work will be required to establish this as the cause, including figuring out the mechanism.

She also suggested it would be good if other groups could replicate the findings seen in these two groups of children from the U.K. I would hope that all other investigators who have reported on these cases outside the U.K. are checking their sequence data for AAV2 sequences as well as doing some genotyping.

The unexplained cases of pediatric hepatitis have ignited heated and even ugly debate on Twitter, with a number of scientists and physicians insisting that those investigating the seeming outbreak were ignoring what appeared to be obvious that the illness was likely a consequence of previous Covid infection.

The efforts to figure out what was behind the cases and whether indeed there was an outbreak underway were complicated by the fact thatdata from the United Statesshowed there had not been an increase in pediatric hepatitis of unknown origin, or liver transplants for pediatric hepatitis, or even of adenovirus 41 infections in the past year compared to prior to the pandemic. That does not mean there might not have been an increase in cases caused by this constellation of triggers, just that the overall number of cases of pediatric hepatitis for which a cause was not found had not changed.

Continued here:
New studies offer theory on cause of unusual hepatitis cases in kids - STAT