Category Archives: Gene Medicine

As activity in this space grows, so do the hurdles in moving these products forward.

Cell and gene therapy (CGT)its risks and promisesare succinctly summarized in this description of clinical trial number NCT01129544, a Phase I/II study in children born with X-linked severe combined immunodeficiency (SCID-X1), an inherited, rare, and life-threatening disease. The eight-person trial, which began in May 2010, continues today. The following paragraph has been edited.1

Gene transfer is still research for two reasons. One, not enough children have been studied to tell if the procedure is consistently successful. [And] we are still learning about its side effects and doing gene transfer safely. In previous trials, five children developed gene transfer-related leukemia; four are in remission; one died.

If the above information has stifled the research communitys scientific curiosity about CGT, it is not evident. Evidence from numerous sourcesClinicalTrials.gov, the Alliance for Regenerative Medicine (ARM), FDAare chock-a-block with studies, trials, and figures showing these therapies popularity. In the second quarter of 2022, 3,633 such treatments were in development, up from 1,745 in May 2021. The vast majority are in the preclinical stage.2,3

Some sources are revealing more.

Most indicate that academics now have a remarkable presence in the CGT development space, including sponsorship. Last year, for the first time, ARM included sponsorship figures in its twice-annual industry report.4 Academic- and government-sponsored trials far exceeded industry for sponsored trials in CGT. Stephen Majors, senior director for public affairs, ARM, says the alliance knew of academias presence for the past few years, but only was able to get data this year from its partner, Global Data.

Less reliable, but still noteworthy, are data from ClinicalTrials.gov: for active Phase I trials, industry has 89; others, which covers academia and government, have 50. Industry enrollment for Phase I is 172; others, 116.Phase III is one for others, eight for industry.

A little disruption in pharmas corner of the world? It seems that way. While basic bench to preclinical to clinical trial has long been the traditional route to FDA approvaland no one interviewed for this article suggested a reroutewhat it does imply is that pharma members have some competition from the spin-offs and academic biotechs that historically they have absorbed.

There are suspected trends that we are watching, says Majors.As to whether academias presence in this spot can be called a trend depends on ones definition of what a trend is. The Centers for Disease Control and Prevention (CDC) considers changes over a number years to determine a trend; financial investment firms typically evaluate over a two-year period.Considering that CGT companies raised $23.1 billion in 2021, 16% more than 2020,3 the answer to the above question could be, maybe.

The CGT space is still immature, according to Mike Rea, founder of Protodigm, a self-described exploratory research organization that partners with biopharma clients on alternative development and commercial solutions. Physicians need time to be comfortable with these therapies, notes Rea, so they may not be used on a regular basis.

For example, physicians have to understand how to deliver the gene, agrees cardiologist Arthur M. Feldman, MD, PhD, whose lab worked on a heart failure-related mutation in BAG3 for decades.

Last month, the company he founded, Renovacor, agreed to be acquired by Rocket Pharmaceuticals.5 We are asking physicians to do something they never did before and to understand a very different set of information, including risk/benefit discussions that they didnt learn about in medical school, he says. Feldman is a Laura H. Carnell Professor of Medicine, Division of Cardiology, and a member of the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine at Temple University.

Chris Learn, Parexels vice president of cell and gene therapy, is unequivocal regarding academias increased presence in the drug development space focused around these treatments. He cites MD Anderson and Moffitt Cancer Center as two institutions that are sponsoring their own trials. The lines are really blurring here, he tells Applied Clinical Trials. It is indisputable.

The following is a look at how academia is showing up in various reports.

In its 2022 report4, ARM separated sponsorship, type of therapygene, cell-based, and tissue engineeringand trial phase. What these data show are industry far exceeding academic and government sponsored trials for gene therapy, while for cell therapy alone, the reverse is true: 656 cell therapy trials for academic and government, and 424 for industry. For gene therapy, there are 84 for the academics and government, and 222 for industry. In a later report, ARM found non-industry trials dropped.

Pharma Intelligences Pharma R&D Annual Review does not break down trials by their sponsors. It does, however, break down whats in the pipeline in various categories, including by the number of therapies per company, and by disease type.6 In numbers captured prior to March 2020, the analysis reported 1,849 companies with asingle drug in its pipeline, up from 1,633 in 2019, comprising more than half of all drug companies. As for types of therapies, gene therapy was in third place, the same spot it occupied in 2019. (Cancer-related therapies occupy the top spots.) Overall, biotech therapies in the pipeline increased by 13.2% in 2020 over 20196,135 vs. 5,422. Cellular therapy, the field in which academia is dominating, rose to 14th place, up from 33.

In 1982, Feldman was a resident in the cardiac care unit at the Johns Hopkins Hospital in Baltimore when he took care of a 22-year-old woman, a native Pennsylvanian, who was dying of heart failure. Sadly, we didnt have drugs with which to treat her, he recalls. Feldmans involvement with the case and the womans family led to his career as a cardiologist, he says. Twenty years later in Philadelphia, he was asked to see a heart-failure patient in consult, who turned out to be the aunt of the younger woman. It would take almost another 10 years until the technology became available to identify the genomic anomaly in this family. Here, a genetic variant that is produced by one of two alleles causes the protein product to be unstable. The result: the cell removes it, so the person with the variant has just half the amount of required protein.

BAG3 is an interesting protein that is found in the heart, the skeletal muscles, and the nervous system, including the brain. Its function is to help remove degraded and misfolded proteins, stop apoptosis or programmed cell death, and maintain the structure of the skeletal muscles. A missing allele isnt the only genetic cause for heart failure, Feldman said. Other patients, while having the correct amount of DNA, have a point mutationa single amino acidin half of the produced DNA. That single letter is the wrong amino acid in the specific site in the protein.

Around this time, Kamel Khalili, PhD, Laura H. Carnell Professor, and chair of the department of microbiology, immunology, and inflammation; director of the Center for Neurovirology and Gene Editing; and director of the Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine, Temple University, had created a method by which he could excise the HIV virus from patients using the new technique of CRISPR-Cas9.

Khalili believes that BAG3 may be involved in the pathogenesis of HIV-1 in brain diseases and protein quality control caused by viral infection as well as several other disorders, including Alzheimers disease and dementia. BAG3 changes the homeostasis of the cell, he says. The only solution is to fix the cell. Khalili has used CRISPR technology to excise the viral genome in both small and large investigational animals and has recently started a Phase I trial to test the safety of the new gene-editing treatment. Khalili, too, started a company, but Temple holds the license. In the case of Renovacor, it was granted the license by Temple.

As a scientist, when you are doing something in biomed research, [the] goal is to translate bench work to the clinic for [the] wellness of people. We are doing long hours and long days because we want to help. We are trying to see if discovery can help people, says Khalili. I know my limit, I stop at business aspects. My interest is to discover research which can help populations.

Was Feldman happy with his business experience? As a company gets bigger, others join the team who fulfill other roles, like acquiring funding or developing the actual product, he says. Releasing the control reins are difficult. But if it speeds up the timeline to get an approved product into the clinic, then its all worth it, he adds.

Researchers such as Feldman and Khalili, says Kaspar Mossman, PhD, director of communications and marketing at QB3, a University of California biotech accelerator, are normally not deeply interested in business. He notes the new flagship space in UC Berkeley called Bakar Lab. So far, it has 25 companies, one-third from university labs. They collaborate, they share equipment, [at times] they merge, Mossman tells Applied Clinical Trials.

And, he adds, Academics tend to be very smart individuals. The more time they spend in business, they learn stuff and become serial founders, says Mossman. They are honest about not wanting to be a CEO.

In terms of business, the academics employers are also pretty smart. The huge bugaboo with CGT commercialization is the manufacturing processthe need for an apheresis unit, ultra-cold storage, and regulated cell processing facilities.

Some institutions are building their own manufacturing facilities to more easily meet the increasingly complicated standards pertaining to regenerative medicine production. Harvard, MD Anderson, Moffitt, the University of Pennsylvania, and the University Hospital of Liege in Belgium8 all have or are planning to build their own facilities.

As for how academias presence impacts the traditional pharma space, those interviewed cited pros and cons. More research is better, more companies vying for venture capital funding is not. But more trials mean more competition among similar therapies, which, says Majors, is a good thing.

We need experimentation, adds Rea. If left to pharma, he says, the research wouldnt happen. Smaller biotechs are taking the risk. Over the last 10 years, Rea believes pharma has been slow in the risk-taking department. Once upon a time, pharma didnt have many competitors. Now, with many numerous smaller companies with viable assets, willing to accept a smaller net profit, the competition is creating some angst. Pharma cant project everyones movement, says Rea. The gene/cell therapy landscape [for products] is huge.

Likely adding to the angst: Those smaller biotechs are getting financial help. Between April 4, 2021, and June 24, 2021, of 23 start-up financing deals, 19 involved academics.2

Learns viewpoint is different. He says there are too many players out there, and while large pharma may be averse to risk, I really do believe what we are witnessing are simply market forces that have played into this. There is so much cash coming in, he continues, that people can be blinded by the pitfalls. The CGT area, he adds, is bloated and he says the industry needs an overall strategy.

Learn doesnt think that academias presence in the CGT space is a flash in the proverbial pan. The enthusiasm to find cures is real, and some research institutions have the endowments to see the trials through. I think it is just the beginning, says Learn. Academia will put their futures in front of them. Why put all your sweat equity into it and not have any fiduciary benefit of the approved product?

In Pharma Intelligences 2020 Pharma R&D Review, its author questioned the wisdom of so many drugs, overall, in the pipeline4,001 added in 2018 and 4,730 added in 2019, for a total of 17,737 drug candidates. [A]re the industrys eyes getting too big for its belly? Unless it can continue to provide [approved therapies] then a certain degree of control in the pipeline might be advisable, the report stated.6

And now to costs. While no one doubts these cures change lives, the question of access persists. FDAs approval of Bluebird Bios second therapy this year, branded as Skysona, for early but active cerebral adrenoleukodystrophy, is expected to cost $3 million. Learn doubts that payers are jumping up and down to get Skysona on their formularies.

Its still a fairly dicey business proposition for companies to invest in this field, Steven Pearson, MD, president of the Institute for Clinical and Economic Review (ICER), said recently.8Theres still a risk that next-generation therapies will not flourish even in developed countries health systems, he added.

One positive development in the US, however, occurred late last month when Congress reauthorized the Prescription Drug User Fee Act (PDUFA) for the next five years, 2023-2027. The action maintained FDAs authority to collect fees from manufacturers and keep and recruit agency staff to review the increased number of CGT applications. Majors says most of FDAs review of CGT products involves scalability and consistent reproducibility in the manufacturing process, which, of course, means traveling.

According to a Senate press release9, FDA is seeking to hire at least 320 new staff members. In a statement, Pharmaceutical Research and Manufacturers of America (PhRMA) said a modern regulatory framework supported by PDUFA helps ensure patients have timely access to lifesaving medicines.

PDUFA reauthorization aside, there is little argument that the field of CGT, from research and drug discovery through commercialization, is advancing rapidly. In turn, so are the unique operational and manufacturing challenges that these therapies present. This reality may thin the currently crowded playing field in CGT going forward, with those sponsors and partners best prepared to deliver on the numerous touchpoints required separating from the pack.

Christine Bahls, Freelance Writer for Medical, Clinical Trials, and Pharma Information

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The Risk-Reward Proposition for CGT Clinical Trials - Applied Clinical Trials Online

Allarity Therapeutics Inc. ALLR is a clinical-stage pharmaceutical company focused on oncology treatments. After decades of research, the company has created what it describes as a powerful next-generation companion diagnostics platform, called Drug Response Predictor (DRP), and is now developing a portfolio of promising cancer treatments.

Companion diagnostic tests help doctors quickly and accurately identify which treatments a particular person is most likely to respond to so that they can develop a personalized treatment plan that has the highest odds of being successful for that cancer patient.

Earlier versions of these tests would look at a single gene or a small handful of genes known to be predictors of treatment response. This can provide a limited view of the patients potential response. Take, for example, the epidermal growth factor receptor (EGFR) expressed in some colorectal cancers.

A test identifying this biomarker might identify the patient as a candidate for anti-EGFR therapy. However, tumors with EGFR alongside KRAS or NRAS mutations are often resistant to anti-EGFR therapy. But if the test isnt looking at that biomarker of resistance, it could misidentify them as a candidate for the therapy when they really arent.

To account for those limitations, the next generation of diagnostic tests is broadening the scope. Foundation Medicine Inc.s FoundationFocus CDx, for example, was the first companion diagnostic assay approved by the Food and Drug Administration (FDA). It analyzes 324 genes to predict responsiveness to treatments for five types of cancer. Similarly, Myriad Genetics Inc. MYGN launched its new Precise Tumor test earlier this year that analyzes over 500 tumor-related genes.

However, these are still constrained by the limits of the biomarkers science has identified so far. That means biomarkers of resistance or responsiveness that researchers dont know about yet could impact the accuracy of the results.

Allaritys Drug Response Predictor (DRP) platform is a unique bioanalytical platform that can create drug-specific predictive diagnostics for a wide range of cancer treatments. Unlike other companion diagnostics on the market, Allaritys DRP looks at the entire 25,000-plus genes expressed in a cancer cell not just the ones science has already identified as biomarkers of responsiveness.

Over the past two decades, the company has developed this platform through dozens of clinical trials and the analysis of thousands of human tumor biopsy samples to create the robust platform. The result is a platform that can bridge the gap between how cancer cells respond to a given drug in vitro versus how actual patient tumors respond. It can then create drug-specific biomarker signatures, a set of 50 to 400 genes that predict how a patients cancer is likely to respond to a specific treatment.

A DRP companion diagnostic delivers its results in the form of a score on a color-coded spectrum where green means the patient is a high match, likely to respond to a drug, and red means the patient is unlikely to respond because they have too many genes predicting resistance to that treatment. In other words, the DRP not only identifies likely candidates for a drug but also rules out unlikely responders so doctors can more effectively narrow in on the best treatment options for each patient.

This precision has yielded promising results in clinical trials. Across the dozens of clinical trials done to develop this platform, DRP has shown it offers twofold to fivefold improvements in overall response rate or time to progression compared to patients not selected with the DRP companion diagnostic. The DRP platform has been extensively published in peer-reviewed scientific journals and is patented.

This genome-wide scope covering all 25,000-plus cancer genes gives Allarity the ability to develop a companion diagnostic for every drug it brings into its pipeline as well as partner with other companies to develop tests for the drugs in their pipelines.

The Massachusetts-based pharmaceutical has minimized the risks associated with drug development by only having acquired drug candidates from other companies, including big pharma, that have already demonstrated safety and efficacy in early trials. Most of Allaritys pipeline programs are former big pharma assets that have progressed past Phase 1 studies or later Phase 2/3 studies.

Stenoparib, for example, is being evaluated as a treatment for ovarian cancer. Allarity licensed it from Eisai Co. Ltd. ESALY. It now planning to evaluate stenoparib in combination with dovitinib, a drug candidate with multiple indications that Allarity licensed from Novartis AG NVS.

Once brought into its pipeline, Allarity uses its DRP platform to develop companion diagnostics alongside each drug to improve the treatments in a personalized medicine approach. Earlier this year, the company refocused its pipeline strategy toward combination therapies in an effort to improve treatment outcomes while also creating more funding and partnership opportunities.

This post contains sponsored advertising content. This content is for informational purposes only and is not intended to be investing advice.

Featured image by Gustavo Fring on Pexels

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Precision Medicine Could Get Even More Precise With Allarity Therapeutics Next-Generation Diagnostics - Benzinga

Your doctor tells you how many times a day you should take a pill, and whether to take it with or without food but they very rarely tell you the exact time at which it has to be taken. Chronopharmacology (also known as chronotherapy or circadian medicine) the idea that a pill popped at exactly the right time has maximum benefit could be a major influence on the future of medicine. Increasing studies are showing that what time of day we treat disease can be crucial, and that its possible to pinpoint the time of day when certain disease is at its worst.

In 1997, doctors in Denver split 59 asthmatics into three groups. The first group used steroid inhalers at 8am every day for four weeks. The second used the same inhalers, but much later in the day, at 5.30pm. The third group dosed four times a day at 7am, 12 noon, 7pm and 10pm at the time, this was believed to be the optimal regime.

After a month, the results were in. The 8am group saw the least improvement, while an inhaler at 5.30pm had similar efficacy to one used at regular intervals. In short, taking a drug once was just as effective as taking it four times, provided you took it at the right time of day.

Professor David Ray of the University of Oxford uses his own inhaler at the time when I think its going to be most effective (the exact time is his secret, as we have to be careful about single-person anecdotes). As co-director of the Sir Jules Thorn Sleep and Circadian Neuroscience Institute, the asthmatic professor has conducted his own research into body clocks and the respiratory disease. He also studies how matching medications with our circadian rhythms can improve the effectiveness of drugs.

Chronopharmacology is a field filled with jaw-dropping studies to whip out at the pub: in 2011, researchers at the University of Birmingham monitored people who had their influenza jabs in the morning versus those who had them in the afternoon. One month on, the patients who received their vaccination between 9am and 11am had higher levels of anti-flu antibodies than patients jabbed between 3pm and 5pm.

Our circadian rhythms are 24-hour cycles of biological activity that are regulated by our internal clocks along with external cues, such as light. You sleep at night not just because your mum told you to, but because when your retina detects light it inhibits the production of the hormone melatonin, stimulating wakefulness. Our body temperature varies by as much as half a degree throughout the day: usually, were coldest at 4am and hottest just in time for the News at Six. Our hormones, immune cells, and organ functions also fluctuate; mouse livers, for example, grow almost 50% in size during the day before shrinking at night.

Many chronobiologists (chrono is the Greek word for time) believe we should use this information to improve medical interventions. Chronotherapy is an unusual field with both a long and short history. On the one hand, way back in 1698, English physician Sir John Floyer noticed that he had asthmatic fits after sleeping and, therefore, by late sitting up I have put by the fit for a night or two.

There are also a number of decades-old groundbreaking studies: the Denver asthma report for one, as well as research undertaken in Canada between 1976 and 1991, which found that children given chemotherapy for their leukaemia in the evening had better disease-free survival rates than those treated in the morning. In some areas, timed medicine is already happening, for instance, many doctors prescribe certain statins drugs for high cholesterol to be taken at night to correspond with the time when your body produces the most cholesterol.

But there is still caution. According to Robert Dallmann, a circadian biologist and biomedical sciences professor at the University of Warwick, the field is in many ways still emerging. There was, for a long time, a feeling that this was all much too complicated, he says. While Floyer might have noticed his asthma worsening at night, he wasnt equipped to know why. Notice was only really taken once the field started to get to the molecular mechanisms underlying lots of this, because before it was mostly a black box, Dallmann says.

In 2017, the Nobel prize in Physiology or Medicine was awarded to three American geneticists who had discovered the molecular mechanisms controlling our biological clocks. In laypersons terms: the scientists had isolated a gene that controls the biological rhythms of fruit flies and found that this gene encodes a protein that accumulates within cells at night and degrades during the day. I think the nominators could see all this exciting science and see that it hadnt really translated into the clinic, says Ray. We are in a quite exciting time now where theres a lot of early-phase work showing what massive potential there is here.

Potential, of course, has pitfalls. If scientists discovered that flu vaccinations are more effective in the morning over a decade ago, then why isnt everyone being jabbed at 9am? Well, first, that would mean the NHS could only issue half as many jabs in a week. Second, it can be hard enough getting people to attend their immunisation appointments at all; limiting them to a narrow window could mean that pregnant women with morning sickness miss their appointment, for example, which is far worse than simply being jabbed in the afternoon. Theres also the fact, Ray says, that health systems are bureaucratic, theyre under financial pressure. Its like a supertanker trying to change course.

And, of course, healthcare providers dont want to jump the gun before enough evidence has accumulated. One 2021 study of 63 healthcare workers in China found that Covid-19 vaccines were more effective when given in the morning. Later that year, a study monitoring 2,190 healthcare workers in the UK found that Covid vaccinations had better efficacy in the afternoon. The vaccinations in both studies were different, but a number of other factors complicate analysis of the results; for example, neither factored in participants medication history or sleep and shift-work patterns.

Then theres the matter of funding. For pharmaceutical companies, there are marketing and safety issues when it comes to producing drugs that should be taken at an exact time of day. What are the risks if someone takes it early or late? Already, approximately 30-50% patients with long-term conditions dont adhere to their medication. But even without new medicine, chronopharmacology can be revolutionary: Ray says the field could rescue drugs that have previously failed clinical trials.

Its not uncommon for a drug to be groundbreaking in mice and ineffective in human trials. But in 2020, researchers from Harvard Medical School published a study which found that preventive stroke strategies that had worked in rodents but failed in humans may have done so because rats are nocturnal. Many trials test rats in the daytime, when theyre inactive, and test humans during the day, when theyre active and awake.

They were able to show that a lot of these promising drugs have probably been tested in humans at the wrong time of day, Ray says. Thats millions and millions and millions of pounds wasted and all those volunteers recruited and subjected to a trial. The time of day a drug is administered could also change its side-effects, so drugs that were written off as too toxic could actually be safe within certain parameters. To save money and save lives, Ray argues that many trials should have clock logic embedded into them.

Lets say you need to take a drug at 8am for it to be effective, and for whatever reason needy kids, a hangover, a fundamental disdain for the morning you cant. Theoretically, says University of Oxford pharmacology professor Sridhar Vasudevan, you could take one drug to change the timing of another problem solved. Chronopharmacology isnt just about matching medicines with your circadian rhythms: its also about creating medicine that affects the circadian system itself.

Vasudevan became interested in circadian rhythms when he worked in psychiatry more than a decade ago. He noticed that sleep disturbance was prevalent across the board in depression, bipolar disorder and schizophrenia. When something goes wrong in the brain that leads to a mood dysfunction, you have associated sleep dysfunction, he says. So, Vasudevan theorised, If you can correct the sleep and circadian dysfunction, you can fix the other side, which is the mood.

In 2016, Vasudevan co-founded a company in the Oxford Centre for Innovation, named Circadian Therapeutics. He and his colleagues are identifying drugs to treat diseases related to circadian rhythm disorders. The team are currently working with blind veterans who have disrupted sleep cycles because light cannot reset their circadian rhythms. Basically, theyre constantly jet-legged every single day, Vasudevan says. The idea is to have a drug that can mimic the effects of light on the brain, so that they can take it once a day and stabilise their sense of time.

Circadian Therapeutics are also developing drugs to help those with neurodegenerative disorders. Sundowning is a phenomenon whereby some people with Alzheimers and Parkinsons become distressed and confused in the late afternoon. Vasudevan is looking into circadian modulators that could manage these symptoms.

Of course we shouldnt just manipulate our body clocks for the sake of it, as Vasudevan warns that taking one newly discovered drug to affect the timing of another could introduce extra risk. Still, theres potential. If the ideal time for you to take a drug is between 1am and 4am, most people are not going to wake up to take it, Vasudevan says, and sleep is extremely important in the healing process, regardless of what youre recovering from. In some circumstances at some point in the future taking one drug to change your circadian timing could help another drug work better.

Drugs are not the only route to a healthy life. Chrono-nutrition and chrono-exercise are exactly what they sound like. In October 2021, a study from Harvard Medical School found that eating earlier affects the speed at which you burn calories and store fat in short, the exact same meal could be far healthier eaten at 5pm than 9pm. In May, academics from Skidmore College in New York found that women who exercised in the morning burned more abdominal fat and reduced their blood pressure more than women who exercised in the evening but, the later exercisers had enhanced muscular performance.

Before you start swallowing 10am pills and going on 3pm jogs, its important to remember that our internal circadian biology does vary: some of us are morning people and some of us are evening people (this characteristic is known as a chronotype). Ray says your chronotype is affected by your age, gender and genes, and argues that in the future well likely see personalised chronopharmacology based on the clock phase of the person, rather than just going off the time on the clock on the wall.

Dallmann, who runs the Patho-Physiological Molecular Clocks Lab at Warwick University, has already used his research to work out what personally works for him. I do implement some of the current knowledge on time-restricted eating, he says, and I choose my painkillers differently by time of day.

Still, its important to remember that for many medicines, the time of day theyre taken doesnt matter at all. As Ray says: If the disease you are targeting doesnt change by time of day then it doesnt matter what time of day you give the drug. If a drug has a long half-life (ie it takes weeks for the substance to reduce by half in your body), then the time of day its taken doesnt matter, because its concentration remains consistent.

Sceptical scientists have also warned about being too enthusiastic. University of North Carolina biochemist Aziz Sancar has argued that when it comes to cancer, chrono-chemotherapy researchers have overstated positive findings and generalised from small studies in the past. But for now and for many, chronopharmacology remains emerging and exciting. We have to be careful about overselling it. It can lead to dissatisfaction if you cry wolf, says Ray. However, Were at that point where its exciting, and people are increasingly aware of the field.

Weve done focus groups with patients, Ray says, and as soon as you say: Wed really like to hear your views about timing and how the time of day affects your disease, theyre over the moon because, finally, someone is listening.

Excerpt from:
Time for your medicine: unlocking the power of our body clocks - The Guardian

The IND for DB-OTO provides clearance for the Company to initiate a pediatric Phase 1/2 clinical trial in the U.S. inchildren and infants, and is part of an international regulatory strategy for clinical development

One-time administration of DB-OTO has resulted in production of otoferlin protein and durable auditory brainstem responses to sound in a congenitally deaf rodent disease model

DB-OTO is Decibels second hearing therapeutic candidate to enter clinical investigation

BOSTON, Oct. 17, 2022 (GLOBE NEWSWIRE) -- Decibel Therapeutics (Nasdaq: DBTX), a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, today announced that it has received clearance from the U.S. Food and Drug Administration (FDA) for its Investigational New Drug (IND) application to initiate a Phase 1/2 clinical trial in pediatric patients of DB-OTO, its lead gene therapy product candidate. DB-OTO is designed to provide durable hearing in individuals born with profound congenital hearing loss due to an otoferlin deficiency.

We are thrilled to work with families, advocacy groups and clinicians in the deaf and hard of hearing community to advance DB-OTO into the clinic, said Laurence Reid, Ph.D., Chief Executive Officer at Decibel. Decibel has assembled a compelling preclinical data package showing that DB-OTO demonstrated a favorable tolerability profile and an ability to stably generate full-length otoferlin transcript, express otoferlin protein and provide hearing in animal models. We are at an exciting time in the development of a new wave of precision gene therapies for children who are deaf and hard of hearing.

DB-OTO is being developed in collaboration with Regeneron Pharmaceuticals and is an adeno-associated virus (AAV)-based, dual-vector, gene therapy product candidate. Otoferlin is a protein expressed in cochlear inner hair cells that enables communication between the sensory hair cells of the inner ear and the auditory nerve. Newborns born with mutations in the otoferlin gene have fully developed structures within the inner ear. However, these newborns have profound hearing loss because signaling between the ear and the brain is disrupted. DB-OTO uses a proprietary, cell-selective promoter to express the otoferlin transgene in hair cells, with the goal of enabling the ear to transmit sound to the brain and provide hearing. DB-OTO received Orphan Drug and Rare Pediatric Disease designations from the FDA in 2021. Currently, there are no approved pharmacologic treatment options for individuals with otoferlin-related hearing loss.

In preclinical studies, Decibel observed that delivery of DB-OTO to the inner ear resulted in production of otoferlin protein and durable auditory brainstem responses to sound in a congenitally deaf, rodent otoferlin disease model. Preclinical studies in non-human primates demonstrated that the local delivery procedure for DB-OTO, an intra-cochlear injection using the surgical approach employed by neurotologists and pediatric otolaryngologists during a standard cochlear implantation procedure, resulted in successful distribution and expression of otoferlin protein across the cochlear length.

The Phase 1/2 dose escalation clinical trial is designed to evaluate the safety, tolerability and efficacy of DB-OTO in pediatric patients with congenital hearing loss due to an otoferlin deficiency. In addition to safety and tolerability endpoints, established, clinically relevant, objective and behavioral measurements of hearing will be used as efficacy endpoints in the clinical trial. The auditory brainstem response, which was used to characterize dose-response of DB-OTO after intra-cochlear delivery in translational studies, will serve as an early, objective, clinically accepted readout of hearing thresholds in the clinical trial.

Otolaryngologists, audiologists and auditory scientists have long awaited the clinical realization of the promise of biological therapies for hearing loss. Gene therapy for congenital deafness represents one such intervention and it would be an understatement to say that clinicians in the field of hearing loss are quite excited to see its advancement into clinical trials, said Jay Rubinstein, M.D., Ph.D., Professor and Virginia Merrill Bloedel Chair in Otolaryngology, Head and Neck Surgery at the University of Washington School of Medicine.

Based on discussions with the FDA during the IND review period, Decibel expects the first two participants in the U.S. portion of the Phase 1/2 trial will be as young as seven years of age and that subsequent participants will include children as young as two years of age and infants younger than two years of age. The Company intends to provide an update on the design of the clinical trial in the future. The DB-OTO IND is part of an international regulatory strategy for development of DB-OTO, which also includes plans to submit one or more Clinical Trial Applications (CTAs) in Europe.

DB-OTO is the second product candidate in Decibels pipeline to advance into clinical testing. In June 2022, Decibel reported positive data from the interim analysis of the Companys Phase 1b clinical trial of DB-020, a novel, proprietary formulation of sodium thiosulfate (STS) designed to protect against hearing loss in cancer patients receiving cisplatin chemotherapy. In the data from the interim analysis, 88% of patients experienced ototoxicity in their placebo-treated ear, and of these patients, 87% were partially or completely protected from ototoxicity in their DB-020-treated ears.

About Decibel TherapeuticsDecibel Therapeutics is a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, one of the largest areas of unmet need in medicine. Decibel has built a proprietary platform that integrates single-cell genomics and bioinformatic analyses, precision gene therapy technologies and expertise in inner ear biology. Decibel is leveraging its platform to advance gene therapies designed to selectively replace genes for the treatment of congenital, monogenic hearing loss and to regenerate inner ear hair cells for the treatment of acquired hearing and balance disorders. Decibels pipeline, including its lead gene therapy product candidate, DB-OTO, to treat congenital, monogenic hearing loss, is designed to deliver on our vision of creating a world of connection for people with hearing and balance disorders. For more information about Decibel Therapeutics, please visit http://www.decibeltx.com or follow us on Twitter.

Forward-Looking Statements

This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, including statements regarding Decibels strategy, future operations, prospects, plans, objectives of management, the therapeutic potential for Decibels product candidates and preclinical programs, the potential benefits of cell-selective expression, plans to submit one or more CTAs in Europe and the expected timeline for initiating a Phase 1/2 clinical trial of DB-OTO constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The words anticipate, believe, continue, could, estimate, expect, intend, may, might, objective, ongoing, plan, predict, project, potential, should, or would, or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Decibel may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the identification and development of product candidates, including the timing of and Decibels ability to obtain approval to initiate clinical development of its program candidates, whether results from preclinical studies will be predictive of the results of later preclinical studies and clinical trials, whether Decibels cash resources are sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements, uncertainties related to the impact of the COVID-19 pandemic on Decibels business and operations, as well as the risks and uncertainties identified in Decibels filings with the Securities and Exchange Commission (SEC), including those risks detailed under the caption Risk Factors in Decibels Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2022 and in other filings Decibel may make with the SEC. In addition, the forward-looking statements included in this press release represent Decibels views as of the date of this press release. Decibel anticipates that subsequent events and developments will cause its views to change. However, while Decibel may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Decibels views as of any date subsequent to the date of this press release.

Investor Contact:Julie SeidelStern Investor Relations, Inc.julie.seidel@sternir.com212-362-1200

Media Contact:Chris RaileyTen Bridge CommunicationsChris@tenbridgecommunications.com617-834-0936

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Decibel Therapeutics Receives FDA Clearance of IND Application for DB-OTO, a Gene Therapy Product Candidate Designed to Provide Hearing to Individuals...

Replay Bio

Replay establishes distinguished Scientific Advisory Board of genomic medicine and cell therapy experts

San Diego, California and London, UK, October 17, 2022 Replay, a genome writing company reprogramming biology by writing and delivering big DNA, today announced that it has established a scientific advisory board (SAB) comprising ten experts across a broad range of areas of scientific importance in genomic medicine and cell therapy.

The newly formed SAB will provide input into Replays strategy, portfolio of next-generation genomic and cell therapy medicines, and associated technology platforms. The SAB complements Replays industry seasoned management team and board.

Adrian Woolfson, Executive Chairman, President and Co-founder of Replay, commented: The multi-disciplinary nature of our scientific advisory board reflects Replays commitment to invoking innovation from a broad range of scientific specialties and leveraging this across our research and development programs. Our new advisors represent some of the best scientific minds of their generation and bring a unique and differentiated portfolio of expertise into the Company. Their contribution to Replay will be invaluable as we continue to address some of the most significant challenges in genomic medicine and cell therapy.

Lachlan MacKinnon, Chief Executive Officer and Co-founder of Replay, added: Following on from our recent launch, the formation of our uniquely distinguished scientific advisory board further demonstrates Replays commitment to developing a cutting-edge portfolio of medicines guided by world-class science. The combined inter-disciplinary expertise of our scientific advisory board brings tremendous knowledge and experience into the Company as we continue to expand our operations, with a view to developing transformative genomic medicines.

Replays SAB will be chaired by Professor Roger Kornberg, PhD, a biochemist whose laboratory work has focused on the molecular basis of eukaryotic transcription and in particular the structure of RNA polymerase and the nucleosome.

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Professor Roger Kornberg, PhD, Chairman of Replays Scientific Advisory Board, said: Replays scientific advisory board incorporates expertise across several areas relevant to Replays genomic medicine and cell therapy technology platforms. I am excited to be working with this exceptional group of scientists and believe we can make a compelling contribution and help Replay realize its vision for genomic medicine.

Replays SAB members are as follows:

Professor Roger D. Kornberg PhD (Chairman), is the Winzer Professor of Medicine in the Department of Structural Biology at Stanford University School of Medicine. He was awarded the Nobel Prize in Chemistry (2006).

Professor Carl H. June, MD, is the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. He is Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania, Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine, and Director of Translational Research at the Abramson Cancer Center. He was the co-founder of TMunity.

Professor Robert S. Langer, ScD, FREng,is one of 12 Institute Professors at the Massachusetts Institute of Technology (MIT), co-founder of Moderna, and was formerly Chair of the FDAs Science Board. He has been awarded 40 honorary doctorates, written over 1,500 articles, and received over 220 awards.

Professor Lynne E. Maquat, PhD, is the J. Lowell Orbinson Endowed Chair and Professor of Biochemistry and Biophysics, University of Rochester Medical Center, and founding Director of the Center for RNA Biology, University of Rochester, Rochester NY. She was awarded the Wolf Prize in Medicine from Israel (2021) and the Warren Alpert Foundation Prize from Harvard Medical School (2021).

Professor Dame Carol Robinson, DBE FRS FMedSci FRSC, is the Dr Lees Professor of Physical and Theoretical Chemistry, the Founding Director of the Kavli Institute for Nanoscience Discovery at Oxford, and a Founder of OMass Therapeutics. She is a Professorial Fellow at Exeter College, Oxford, and was formerly President of the Royal Society of Chemistry.

Professor David V. Schaffer, PhD, is the Hubbard Howe Professor of Chemical and Biomolecular Engineering, Bioengineering, and Neuroscience at the University of California, Berkeley, where he is Director of theBakar BioEnginuity Hub and Director of the California Institute for Quantitative Biosciences (QB3). He was the co-founder of 4D Molecular Therapeutics, Ignite Immunotherapies, Rewrite, and 5 additional companies.

Professor Stuart L. Schreiber, PhD, is the Morris Loeb Professor of Chemistry and Chemical Biology at Harvard University. He is a co-founder of the Broad Institute at Harvard University and MIT and co-founder of Harvards Institute of Chemistry and Cell Biology. He was awarded the Wolf Prize in Chemistry (2016).

Professor Pamela Silver, PhD, is the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology in the Department of Systems Biology at Harvard Medical School, and a founding member of the Wyss Institute for Biologically Inspired Engineering at Harvard Medical School.

Professor Sir John E. Walker, FRS FMedSci, is Emeritus Director and Professor at the MRC Mitochondrial Biology Unit at the University of Cambridge, England, and a fellow of Sidney Sussex College, Cambridge. He was awarded the Nobel Prize in Chemistry (1997).

Professor John Fraser Wright, PhD, is Professor of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, and Director of Technology Innovation at the Center for Definitive and Curative Medicine at Stanford University. He is co-founder and was Chief Technology Officer at Spark Therapeutics and is co-founder and Chief Scientific Advisor at Kriya Therapeutics.

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About Replay

Replay is a genome writing company, which aims to define the future of genomic medicine through reprogramming biology by writing and delivering big DNA. The Company has assembled a toolkit of disruptive platform technologies including a high payload capacity HSV platform, a hypoimmunogenic cell therapy platform, and a genome writing platform to address the scientific challenges currently limiting clinical progress and preventing genomic medicine from realizing its full potential. The Companys hub-and-spoke business model separates technology development within Replay from therapeutic development in product companies that leverage its technology platforms. For example, Replays synHSV technology, a high payload capacity HSV vector capable of delivering up to 30 times the payload of AAV, is utilized by Replays four gene therapy product companies, bringing big DNA treatments to diseases affecting the skin, eye, brain, and muscle. The Company has, additionally, established an enzyme writing product company that leverages its evolutionary inference machine learning and genome writing technology to optimize enzyme functionality. Replay is led by a world-class team of academics, entrepreneurs, and industry experts.

The Company raised $55 million in seed financing in July 2022 and is supported by an international syndicate of investors including: KKR, OMX Ventures, ARTIS Ventures, and Lansdowne Partners.

Replay is headquartered in San Diego, California, and London, UK. For further information please visit http://www.replay.bio and follow us on LinkedIn and Twitter.

Contacts:

Replay

Dr Adrian Woolfson/Lachlan MacKinnon

info@replay.bio

Consilium Strategic Communications Media relations

Amber Fennell/Tracy Cheung/Andrew Stern

replay@consilium-comms.com

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Replay establishes distinguished Scientific Advisory Board of genomic medicine and cell therapy experts - Yahoo Finance

Summary: Some senescent (zombie) cells are embedded in young, healthy tissue and promote normal repair from damage, researchers say.

Source: UCSF

Not all senescent cells are harmful zombies that should be wiped out to prevent age-related disease, according to new research from UC San Francisco, which found that some of them are embedded in young, healthy tissues and promote normal repair from damage.

Scientists have now seen these cells in action in lung tissue, as well as other organs that serve as barriers in the body, such as the small intestine, colon and skin. When they used drugs called senolytics to kill these cells, injuries to lung tissues healed more slowly.

Senescent cells can occupy niches with privileged positions as sentinels that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair, said Tien Peng, MD, associate professor of pulmonary, critical care, allergy and sleep medicine, and senior author of the study, which appears inScienceon October 13, 2022.

Aging cells can both damage and heal

Peng said it was understandable that scientists at first viewed senescent cells as purely detrimental. As people age, senescent cells accumulate that have characteristics of old, worn-out cells, including the inability to make new cells.

Instead of dying like normal aged cells, they to live on, spewing a cocktail of inflammatory compounds that form the senescence associated secretory phenotype (SASP). These factors are linked to Alzheimers disease, arthritis, and other age-related maladies including cancer.

The catchy name zombie cells was coined for them.

Using senolytics that target and kill zombie cells, researchers made the exciting discovery that clearing senescent cells from animals thwarted or diminished age-related disease and extended the lifespan of the animals. Thereafter, a boom of activity ensued in research labs and pharmaceutical companies focused on discovering and refining more powerful versions of these drugs.

But killing off senescent cells has dangers, Peng said. For one thing, this current study showed that senescent cells also possess the ability to promote normal healing through activation of stem cell repair.

Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behavior, said Peng.

Lighting up senescent cells

One major challenge to studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite sparse, making it difficult to detect the cells.

In early experiments, researchers extracted cells called fibroblasts into culture dishes, allowing them to grow and produce enough cells to experiment with, and then stressed the cells with chemicals that induced them to become senescent. But in living organisms, cells interact with tissues around them, strongly affecting the cells gene activity.

This means that the characteristics of cells growing isolated in a glass dish could be quite different from that of cells in their natural environment.

To create a more powerful tool for their studies, postdoctoral scholar Nabora Reyes de Barboza, Ph.D. and colleagues improved on a common technique of fusing a relevant genein this case, the p16 gene, which is overly active in senescent cellswith green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light.

By enhancing the quantity and stability of green fluorescent protein in these senescent cells, Reyes greatly amplified the fluorescent signal, finally enabling the researchers to see senescent cells in their natural habitat of living tissues.

Zombies stimulate stem cells shortly after birth

Using this highly sensitive tool, the researchers found that senescent cells exist in young and healthy tissues to a greater extent than previously thought, and actually begin appearing shortly after birth.

The scientists also identified specific growth factors that senescent cells secrete to stimulate stem cells to grow and repair tissues.

Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.

In their studies of lung tissue, Pengs team observed green glowing senescent cells lying next to stem cells on the basement membrane that serves as a barrier preventing foreign cells and harmful chemicals from entering the body and also allows oxygen to diffuse from air in the lungs into underlying tissues. Damage can occur at this dynamic interface.

The team saw senescent cells in similar positions in other barrier organs such as small intestine, colon, and skin, and their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells were not able to properly repair the barrier surface.

Leanne Jones, Ph.D., director of the UCSF Bakar Aging Research Institute and Stuart Lindsay Endowed Professor in Experimental Pathology, said Pengs study is truly significant for the field of aging research, where the goal is to help individuals live longer and more healthy lives.

The studies suggest that senolytics research should focus on recognizing and precisely targeting harmful senescent cells, perhaps at the earliest signs of disease, while leaving helpful ones intact, she said.

These findings emphasize the need to develop better drugs and small molecules that will target specific subsets of senescentcellsthat are implicated in disease rather than in regeneration.

Additional authors include Nabora Reyes, Maria Krasilnikov, Nancy C. Allen, Jinyoung Lee, Ben Hyams, Minqi Zhou, Supriya Ravishankar, Monica Cassandras, Chaoqun Wang, Imran Khan, Michael Matthay, and Dean Shappard from the Department of Medicine, Pulmonary and Critical Care Division, Peri Matatia and Ari Molofsky from the Department of Laboratory Medicine, Makato Nakanishi of University of Tokyo, and Judith Campisi of the Buck Institute.

Author: Press OfficeSource: UCSFContact: Press Office UCSFImage: The image is in the public domain

Original Research: Closed access.Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung by Nabora Reyes de Mochel et al. Science

Abstract

Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung

We engineered an ultrasensitive reporter ofp16INK4a, a biomarker of cellular senescence.

Our reporter detectedp16INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung.

Furthermore, thesep16INK4a+fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration.

In addition,p16INK4aexpression was required in fibroblasts to enhance epithelial regeneration.

This study highlights a role forp16INK4a+fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.

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Scientists Reappraise the Role of Zombie Cells That Anti-aging Medicine Has Sought to Eliminate - Neuroscience News

COLUMBUS, Ohio--(BUSINESS WIRE)--Forge Biologics, a gene therapy-focused contract development and manufacturing organization, announced today that Chief Medical Officer Maria Escolar, M.D, MS., will present updated clinical data from the RESKUE Phase 1/2 clinical trial for FBX-101the Companys novel gene therapy for the treatment of patients with Krabbe diseaseduring the 29th Congress of the European Society of Gene & Cell Therapy (ESGCT) being held October 11-14, 2022, in Edinburgh, Scotland.

RESKUE is the first-in-human clinical trial where patients with Krabbe disease are administered FBX-101, a systemic adeno-associated virus (AAV) gene replacement strategy, after full myeloablation and hematopoietic stem cell transplantation (HSCT). Krabbe is a rare, genetic, neurodegenerative leukodystrophy affecting the central nervous system (CNS) and peripheral nervous system (PNS). Krabbe disease affects infants with an incidence rate of 1-2.5 in 100,000 and leads to premature death, often by 2 years of age. Clinical data support preclinical observations that this gene therapy approach after HSCT may lessen many of the immune challenges previously observed with systemic AAV gene delivery and may create a safer environment for gene replacement. Findings also support this novel approach for extending the delivery of gene replacement strategies to target metabolic diseases amenable to HSCT.

The data from treated subjects demonstrate that intravenous FBX-101 after HSCT has been safe and well tolerated. Notably, the data indicate an absence of humoral immune response against the systemically delivered AAV, and significantly increased galactocerebrosidase (GALC) enzyme activity is observed in plasma and cerebrospinal fluid (CSF). Krabbe disease is characterized by mutations in the GALC gene which lead to loss of motor function. All subjects treated to date have also exhibited improved motor activity and normal brain development, which would not be anticipated in the absence of systemic gene transfer of the GALC gene.

We are excited to present the data from multiple patients in our RESKUE trial and encouraged by the safety and efficacy results observed in FBX-101 treated subjects, stated Dr. Escolar. An update on our first cohort data demonstrates that intravenous FBX-101 after HSCT was safe and well tolerated, including increased GALC enzyme activity in plasma and CSF, normal myelination of white matter, and normalization of motor development. The results are exciting and give us hope for patients suffering from Krabbe disease who typically do not live past two years of age untreated.

Dr. Escolars presentation, Intravenous FBX-101 (AAVrh10.hGALC) following Hematopoietic Stem Cell Transplantation increases GALC activity, supports brain development and improves motor function in patients with Infantile Krabbe Disease: RESKUE Phase 1/2 Clinical Trial, will be available for all ESGCT attendees on October 11, 2022, and through October 14th. For more details on the conference, please visit: https://www.esgctcongress.com/

Timothy J. Miller, Ph.D., CEO, President, and Co-Founder of Forge, will also share the clinical data during a Company presentation on Wednesday, October 12, 2022, 9:15 a.m. PT, at the Alliance for Regenerative Medicines (ARM) Cell & Gene Meeting on the Mesa, in Carlsbad, CA. The annual meeting is taking place October 11-13, 2022. More details on the conference can be found on ARMs website: https://alliancerm.org/arm-event/meetingonthemesa/

About Krabbe Disease

Krabbe disease is a rare neurodegenerative disease affecting about 1-2.5 in 100,000 people in the U.S. Krabbe disease is caused by autosomal recessive mutations in the galactocerebrosidase (GALC) gene, an enzyme responsible for the breakdown of certain types of sphingolipids, such as psychosine, associated with myelination of the nervous system. Without functional GALC, psychosine accumulates to toxic levels in cells, specifically in cells insulating the nerves in the brain and peripheral nervous system, causing rapid demyelination. Krabbe disease initially manifests as irritability, developmental delay, and progressive muscle weakness; symptoms rapidly advance to difficulty swallowing, breathing, worsening developmental delay, and vision and hearing loss. Infantile Krabbe disease (0 12 months of age at onset) usually leads to death in untreated patients by 2 years of age. Late Infantile patients (12-36 months of age at onset) usually die by the age of six. The current standard of care, hematopoietic stem cell transplantation (HSCT), has been shown to stabilize cognitive decline and significantly improve long-term neurological outcomes when performed prior to symptom onset. However, HSCT does not correct the peripheral neuropathy that is progressive as the patient grows, leading to loss of gross motor skills and eventually death. Early diagnosis is key for treating Krabbe patients before significant neurological damage has occurred. Currently, 10 states in the USA are conducting newborn screening for Krabbe disease. Infants who screen positive, meaning insufficient GALC activity is detected, undergo psychosine and mutation analysis to confirm the diagnosis and predict disease onset.

About FBX-101

FBX-101 was developed to treat children with Krabbe disease. FBX-101 is an adeno-associated viral serotype rh10 (AAVrh10) gene therapy that is delivered intravenously after HSCT. The vector delivers a functional copy of the GALC gene to cells in both the central and peripheral nervous system. FBX-101 has been shown to functionally correct the central and peripheral neuropathy associated with Krabbe, improve gross motor outcomes, and significantly prolong lifespan in animal models. This approach has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies and extend the duration of gene transfer.

About the RESKUE Trial

RESKUE a Phase 1/2 clinical trial to investigate the safety and efficacy of FBX-101 in patients with Infantile Krabbe disease. It is a nonblinded, non-randomized dose escalation study of intravenous AAVrh10 after HSCT, in which subjects receive standard of care hematopoietic cell transplantation for Krabbe Disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be used to compare as control group. More information on the RESKUE trial can be found online at https://www.clinicaltrials.gov/ct2/show/NCT04693598.

About Forge Biologics

Forge Biologics is a hybrid gene therapy contract manufacturing and clinical-stage therapeutics development company. Forges mission is to enable access to life changing gene therapies and help bring them from idea to reality. Forges 200,000 square foot facility utilizes 20 cGMP suites in Columbus, Ohio, the Hearth, to serve as its headquarters. The Hearth is a custom-designed cGMP facility focused on AAV manufacturing and can host end-to-end manufacturing services to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing. By taking a patients-first approach, Forge aims to accelerate the timelines of these transformative medicines for those who need them the most. To learn more, visit http://www.forgebiologics.com.

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Forge Biologics Announces Updated Positive Clinical Data in RESKUE, a Novel Phase 1/2 Gene Therapy Trial for Patients with Krabbe Disease - Business...

The phase 1b Study 116/KEYNOTE-524 trial of lenvatinib and pembrolizumab revealed the RAS gene signature to possibly be associated with progression-free survival in unresectable hepatocellular carcinoma.

The RAS gene signature is potentially associated with progression-free survival (PFS) from combination treatment with lenvatinib (Lenvima) and pembrolizumab (Keytruda) in patients with unresectable hepatocellular carcinoma (HCC) when accounting for T-cellinflamed gene expression profile (GEP), according to an exploratory analysis from the phase 1b Study 116/ KEYNOTE-524 trial (NCT03006926).1

Otherwise, no statistically significant associations were reported between gene expression signatures and PFS or objective response rate (ORR) before adjusting for T-cellinflamed GEP.

Study authors, led by Richard S. Finn, MD, professor of medicine at David Geffen School of Medicine at University of California, Los Angeles, presented the results in a poster at the 2022 International Liver Cancer Association Conference.1

The multicenter, open-label Study 116/KEYNOTE-524 trial was a dose-finding and dose-expansion study exploring the use of lenvatinib plus pembrolizumab in patients with unresectable HCC who had no prior systemic treatment and had Barcelona Clinic Liver Cancer stage B or C disease. Patients (n = 104) received 8 or 12 mg of daily lenvatinib, depending on the patients weight, and 200 mg of intravenous pembrolizumab once every 3 weeks.

The ORR by independent imaging review was 36.0% per RECIST 1.1 criteria and 46.0% per modified RECIST criteria. The median duration of response was 12.6 months by RECIST criteria and 8.6 months by modified RECIST criteria. The median PFS was 8.6 months and 9.3 months by RECIST and modified RECIST criteria, respectively. The median overall survival was 22 months.2

Ninety-five percent of patients experienced 1 or more treatment-related adverse event, with the most common being hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), and hypothyroidism (25%). The only grade 4 event reported was leukopenia/neutropenia.

After receiving a breakthrough therapy designation for the combination, the developers submitted an application for the regimen. Despite the clinically meaningful efficacy seen with the regimen in the Study 116/KEYNOTE-524 trial, the FDA issued a complete response letter for the indication because it followed shortly after the approval for atezolizumab (Tecentriq) plus bevacizumab (Avastin).3

Exploratory analyses have since sought to identify possible biomarkers of response to the treatment regimen. In the analysis from Finn et al, investigators analyzed RNA sequencing data in 40 patients from the study for an 18-gene T-cellinflamed GEP and 11 different noninflamed signatures to determine possible associations between these gene expression signatures and posttreatment clinical outcomes.

Analysis was completed using logistic regression and Cox proportional hazard regression models with a 1-sided P value for the T-cellinflamed profile and 2-sided for all other signatures. The prespecified level for significance was set at = 0.05.

Of the evaluable patients, the median age was 65.5 years (range, 47-81) and 75% of patients were male. Sixty percent of the patients were White, 10% were Asian, 5% were Black or African American, and the remainder were unknown, other, or not reported. The ECOG performance status was 0 in 48% of patients and 1 in 53%. Thirty-five percent of the group were responders to the treatment regimen, with an ORR of 35% (95% CI, 21%-52%), including a complete response in 10%. The median PFS in the group was 7.7 months (95% CI, 4.4-9.9).

Evaluated P values for associations with gene expression signatures are included in the TABLE1 both before and after adjustment for T-cellinflamed GEP. Most notably, the P value for association with RAS and PFS was statistically significant at .003 after adjustment for T-cellinflamed GEP.

The patient-level area under the receiver operating characteristic curve (AUROC) score was 0.55 (95% CI, 0.36-0.75) by response status. Per gene expression signature, the AUROC by response rate was 0.34 (95% CI, 0.15-0.53) for the angiogenesis signature, 0.35 (95% CI, 0.16-0.54) for the granulocytic myeloid-derived suppressor cell signature, 0.46 (95% CI, 0.26-0.67) for the monocytic myeloid-derived suppressor cell signature, and 0.41 (95% CI, 0.22-0.61) for the glycolysis signature. With the hypoxia gene expression signature, the AUROC was 0.36 (95% CI, 0.17-0.55), 0.55 (95% CI, 0.5-0.75) for the microvessel density signature, 0.34 (95% CI, 0.16-0.52) for the MYC signature, and 0.44 (95% CI, 0.24-0.64) for the proliferation signature. The RAS signature showed an AUROC of 0.38 (95% CI, 0.18-0.58), 0.48 (95% CI, 0.28-0.68) for the stroma/epithelial-to-mesenchymal transition/transforming growth factor signature, and 0.51 (95% CI, 0.31-0.71) for the WNT pathway signature.

Finn et al noted in their poster that findings from the analysis require further validation in larger cohorts, and that efforts are ongoing to identify biomarkers of response for patients with advanced HCC.

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Gene Expression Signatures Are Analyzed for Biomarkers of Response in HCC - Targeted Oncology

The NHS will be able to diagnose and potentially save the lives of thousands of severely ill children and babies within days rather than weeks with a world-first national genetic testing service launching today.

Announcing the groundbreaking new service at the first-ever NHS genomics conference in England, NHS chief executive Amanda Pritchard hailed it as the start of a new era of genomic medicine.

The new service, based in Devon, will rapidly process DNA samples of babies and children who end up seriously ill in hospital or who are born with a rare disease, such as cancer.

It will benefit more than 1,000 little ones in intensive care every year who until now had to undergo extensive levels of tests, with results often taking weeks to come back.

Now, they will be able to have simple blood tests and once they are processed, the service will give medical teams from across the country results within days meaning they can kickstart lifesaving treatment plans for more than 6,000 genetic diseases.

Whole genome sequencing works by looking for changes in genes in the seriously ill childs DNA. This can help rapidly determine a diagnosis, opening up the possibility for thousands more patients to have their conditions cured completely.

Other patients with more complex illnesses will have the best possible chance of reducing difficult complications sooner, boosting their quality of life.

The trail-blazing service based in Exeter, launched as part of the NHS Genomics Strategy at the inaugural Genomics Healthcare Summit in London, is another example of the NHS leading the world in harnessing the potential of genomic medicine to transform patient care.

Amanda Pritchard, NHS chief executive, said: This global first is an incredible moment for the NHS and will be revolutionary in helping us to rapidly diagnose the illnesses of thousands of seriously ill children and babies saving countless lives in the years to come.

I have seen how these simple blood tests can change the lives of babies and their families and being able to expand this further, is wonderful for children and their families.

When a child comes to intensive care timing is everything, so finding the right diagnosis and treatment as quickly as possible is absolutely vital, and I am delighted that the pioneering work of the NHS Genomic Medicine Service is transforming the way we diagnose and treat patients in England.

The NHS is recognised worldwide as a world leader in genomics, and this new service proves just that it also builds on our Long Term Plan commitment to deliver the most medically advanced services possible for all our patients boosting the life chances of thousands across the country.

Seven-month-old Reuben, from Cheltenham, Gloucester, was saved by the service while it was being trialled in March ahead of it being offered nationally.

Five-day-old Reuben had been fighting for his life at Bristol Royal Hospital for Children after being admitted with sickness and lethargy. Here doctors battled to filter potentially lethal levels of ammonia which had been detected in his blood.

Dad Atsushi, 39, said: When the doctor came out and told us that they were doing everything they could keep him alive, what we were facing really dawned on us.

We saw him connected to 20, 30 tubes and it was really tough to see.

Doctors suspected urea cycle disorder, but tests were inconclusive. But thanks to the trial of the rapid whole genome sequencing service, his blood could be tested rather than an invasive and potentially dangerous liver biopsy.

Genetic changes in the CPS1 gene were found, meaning his body could not break down nitrogen which in turn caused toxic levels of ammonia in the blood.

The correct medication was quickly given to Reuben without which he could have died. After two and half months in hospital, he was discharged and he is now doing well and waiting to have a liver transplant that will cure his condition.

Mum Eleanor, 38, said: All the care Reuben received would not have happened as quickly and his early diagnosis meant we knew what to expect.

Were so grateful for everything the NHS has done to enable this to happen and the incredible genomic testing we have had.

Atsushi added: Were grateful that despite the difficult times, we never felt alone and we knew we had the NHS teams with us at every step and now we look to the future with hope.

One in 17 people in England will develop a rare disease during their lifetime and more than 80% of these are genetic in origin.

About three-quarters of rare genetic disorders will present during childhood and are responsible for almost a third of neonatal intensive care deaths.

In 2021, the NHS became the first national healthcare system in the world to begin offering whole genome sequencing routinely for children, and some adults, with certain cancers.

This has led to the launch today of the National Rapid Whole Genome Sequencing Service, based in the South West NHS Genomic Laboratory Hub at Royal Devon University Healthcare NHS Foundation Trust.

Dr Emma Baple, who runs the National Rapid Whole Genome Sequencing Service, said: The rapid whole genome testing service will transform how rare genetic conditions are diagnosed.

We know that with prompt and accurate diagnosis, conditions could be cured or better managed with the right clinical care, which would be life-altering and potentially life-saving for so many seriously unwell babies and children.

This new service, which has been over five years in the making, is a huge step-change in what we can do for these children and their families, and it is an absolute privilege for us to play a part in helping to give children up and down the country the best care possible.

The NHS chief executive is also expected to announce the launch of the NHS first Genomics Strategy a five-year plan to step up the use of genomic medicine within the NHS embedding the cutting-edge benefits it delivers to patients in all areas of the NHS from cancer to inherited and rare diseases.

The plan will help more people receive life-saving diagnoses and get the support and cutting-edge treatments needed to live with them.

Key commitments made in the plan include:

The establishment of a NHS GMS Ethics Advisory Board to consider the introduction of new technologies, return of results, data protection and genomic research.

The expansion of genomic testing into the NHS diagnostic infrastructure for genomic testing. For example, exploring the role that Community Diagnostics Centres could play alongside the NHS GMS across a number of areas, including the collection of samples from family members for inherited disease genomic testing.

Upskilling the NHS workforce to help embed the benefits of genomics across the NHS including the development of a Genomic Training Academy

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NHS England World-first national genetic testing service to deliver rapid life-saving checks for babies and kids - NHS England

Ascl1, a gene activity-controlling protein recognized to be a vital protein involved in the conversion of fibroblasts to neurons, has been found to be the key to a novel cardiomyocyte-creating technology. Ascl1 was previously assumed to be neuron-specific by researchers. Researchers at the University of North Carolina School of Medicine (USA) have made tremendous progress in the promising field of cellular reprogramming and organ regeneration, and the discovery may have a significant impact on future treatments for damaged hearts.

In a study published in the journal Cell Stem Cell, researchers at the University of North Carolina (UNC) at Chapel Hill havedeveloped a faster and more efficient approach for converting scar tissue cells (fibroblasts) intohealthy cardiac muscle cells (cardiomyocytes). Fibroblasts are responsible for the fibrous, stiff tissue that leads to heart failure following either a heart attack orheart disease. Transforming fibroblasts into cardiomyocytes is currentlybeing studied as a promising avenue for the treatment or possibly acure for this prevalent and fatal condition.

Remarkably, the secret to the novel cardiomyocyte-creating process turned out to be Ascl1, a gene activity-controlling protein known to be an important protein in the conversion of fibroblasts to neurons. Ascl1 was previously assumed to be neuron-specific by researchers.

Its an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming, comments the study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine.

Over the last 15 years, scientists have devised multiple strategies for reprograming adult cells to become stem cells, then stimulating those stem cells to transform intoadult cells of a different type. Scientists have now discovered atechniqueto perform this reprogramming more immediately,from one mature cell type to another. The aim has been that if these procedures are made as safe, effective, and efficient as possible, clinicians would be able to employ a simple injection into patients to convert harmful cells into helpful ones.

Reprogramming fibroblasts has long been one of the important goals in the field, Qian said. Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.

In this novel study, Qians team reprogrammed mice fibroblasts into cardiomyocytes, liver cells, and neurons using three known techniques. Their goal was to document and compare changes in gene activity patterns and gene-activity regulatory factors in cells across these three different approaches.

Surprisingly, the researchers discovered that converting fibroblasts into neurons triggered a group of cardiomyocyte genes. It was quickly realized that this activation was caused by Ascl1, one of the master-programmer transcription factor proteins required to createneurons.

Because Ascl1 activated cardiomyocyte genes, the researchers decided to add it to the three-transcription-factor combination they were employing to produce cardiomyocytes to examine the effects. The scientists wereshocked to see a more than ten-fold increase in the effectiveness of reprogramming (the fraction of successfully reprogrammed cells). Additionally, it was elucidated that they could now exclude two of the three components from their original combination, keeping simply Ascl1 and another transcription factor known as Mef2c.

Further research revealed that Ascl1 activates both neuron and cardiomyocyte genes on its own but shifts away from the pro-neuron function when Mef2c is present. Ascl1 activates a wide range of cardiomyocyte genes in collaboration with Mef2c.

Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail, Qian stated.

These findings indicate that the primary transcription factors employed in direct cellular reprogramming are not necessarily restricted to a single cell type. Perhaps even more crucially, these findings are another step forward in the development of future cell-reprogramming medicines for major diseases. Qian and her colleagues seek to develop a two-in-one synthetic protein that comprises the active portions of both Ascl1 and Mef2c, whichmay be injected into failing hearts to repair them.

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The proteinprotein relationship that could mend a broken heart - RegMedNet