Category Archives: Gene Medicine

(Aylish Turner | Daily Trojan)

A mutation in a newly discovered microprotein might lead to a significant risk for Alzheimers disease, according to research from the Leonard Davis School of Gerontology. The discovery expanded the gene target to treat the disease and provided a new potential therapeutic solution to the incurable disease.

The newly-discovered protein, named SHMOOSE, is encoded by a gene that exists within the cells mitochondria, which is responsible for cells energy production. A mutation within this gene, which partially inactivates the SHMOOSE microprotein, is associated with a 30% increase in ones risk of developing Alzheimers disease. The mutated version of the protein has reportedly appeared within nearly a quarter of people of European ancestry.

Brendan Miller, a 2022 doctoral graduate who studied neuroscience and the studys first author, relied on big data techniques to identify genetic variations associated with disease risk, after analyses revealed that mutations are linked to increased risk of Alzheimers, brain atrophy and energy metabolism.

Researchers began studying the genes mutated and default forms and found that SHMOOSE is the first mitochondrial-DNA-encoded microprotein to be detected using both antibodies and mass spectrometry.

Miller said one of the biggest obstacles in the research process was the sheer amount of data that researchers had to compile to make these findings. Miller described this big data as taking up terabytes of storage, containing research gleaned from dozens of individuals. His team was able to overcome this by utilizing new and advanced technology, which allowed them to make discoveries not otherwise possible.

Computational power over the last ten years has grown exponentially. With that means youre going to see in the field of medicine and biology a lot of rapid discoveries, Miller said. At USC, we have infrastructure, and we have a lot of talented computational scientists to help us with that.

Being able to manipulate and understand big data was essential for the success of this project, Miller said.

The big challenge is starting from hundreds of potential gene targets and narrowing them down to one, Miller said. The way we did this was [by] implementing a lot of genetics data and omics data from similar individuals with different data types.

The study highlights the importance of the emerging field of microprotein studies. Microprotein, a small protein encoded from a small open reading frame, appears to modify energy signaling and metabolism in the central nervous system. A variety of studies have found microproteins in mitochondria of neurons and showed that SHMOOSE alters energy metabolism in the brain, in part by inhibiting the inner mitochondrial membrane.

When you look at microproteins, there are many hundreds of thousands of them, [which] creates a whole new dimension of things that need to be discovered, said Pinchas Cohen, a professor of gerontology, medicine and biological sciences and the senior author of the study.

There is currently no approved medicine for Alzheimers disease developed based on microproteins, while microprotein- or peptide-related treatments have been employed in treatments of diabetes, heart diseases and some other chronic illnesses. The therapeutic potential of microproteins in Alzheimers cases was thus exciting news for many researchers in the field.

Helena Chang Chui, chair and professor of neurology at Keck School of Medicine, said the paper is very rich and has significant potential impact for understanding the causes of Alzheimers.

Were getting a little bit closer with immunological approaches with monoclonal antibodies[and] antibodies against amyloid proteins, but theres been no particular no peptide treatments, Chui said.

Researchers are, on the whole, cautiously optimistic about the therapeutic potential of the study, Cohen said, and it is still too early to contemplate applying the findings of the study into therapeutic research. Cohen said he hopes that the team could use standard mouse models of Alzheimers and demonstrate that SHMOOSE does have benefits on the treatment of Alzheimers disease.

Then, as Cohen implied, the team might pick individuals who have the SHMOOSE mutation to do the research, which will lend to the precision medicine approaches.

The issue is that Alzhmeimers disease is very heterogeneous. [Its] not really one specific condition, its multiple conditions, each being a result of various genetic susceptibilities, that all present in a similar way, Cohen said. Thats why I believe that treatments that will be focused on the primary genetic abnormality, also known as precision medicine approaches, will be more efficacious.

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Study finds microprotein correlated to Alzheimers risk - Daily Trojan Online

Passage Bio

PHILADELPHIA, Oct. 10, 2022 (GLOBE NEWSWIRE) -- Passage Bio, Inc. (Nasdaq: PASG), a clinical-stage genetic medicines company focused on developing transformative therapies for central nervous system (CNS) disorders, today announced the appointment of William Chou, M.D. as chief executive officer (CEO) and a member of the board, effective immediately. Edgar B. (Chip) Cale will resign his position as the companys interim CEO and will continue in his role as general counsel and corporate secretary. Maxine Gowen, Ph.D., will step down as interim executive chairwoman following a brief transition period and will then continue to serve as chairwoman.

The Board and I are delighted to welcome Will to Passage Bio to lead the company through an exciting phase of development, said Dr. Gowen. Wills depth of experience and success in developing and commercializing advanced therapeutics will be instrumental in establishing and solidifying the company as a leader in genetic medicines.

Dr. Chou is an accomplished executive with nearly twenty years of healthcare experience across a range of development and commercialization roles. Most recently, Dr. Chou served as CEO of Aruvant Sciences, a clinical-stage biopharmaceutical company focused on developing gene therapies for rare diseases.

I am thrilled to join the talented team at Passage Bio and build upon the companys many accomplishments and impressive capabilities, said Dr. Chou. With three ongoing clinical programs, we are poised to deliver multiple meaningful milestones over the coming quarters. As a clinician, it is my privilege to lead a company with tremendous potential to bring transformative therapies to patients with CNS disorders for which there are limited or no approved treatment options today.

Prior to joining Aruvant, Dr. Chou served in a variety of leadership roles at Novartis, including vice president, global disease lead for Novartis Cell and Gene Therapy unit where he oversaw the global commercial launch of Kymriah, the first CAR-T cell therapy. Prior to that role, Dr. Chou led the Kymriah lymphoma clinical development program to approvals in the United States, Europe, Australia, Canada and Japan. Before joining Novartis, Dr. Chou worked at the Boston Consulting Group where he focused on commercial and clinical pharmaceutical strategy.

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Dr. Chou holds an M.B.A. from the Yale School of Management, an M.D. from the University of Pittsburgh School of Medicine, and an A.B. in politics and economics from Princeton University. Dr. Chou completed his residency in internal medicine at Yale New Haven Hospital and his fellowship in geriatrics at Yale University.

About Passage Bio

Passage Bio (Nasdaq: PASG) is a clinical-stage genetic medicines company on a mission to provide life-transforming therapies for patients with CNS diseases with limited or no approved treatment options. Our portfolio spans pediatric and adult CNS indications, and we are currently advancing three clinical programs in GM1 gangliosidosis, Krabbe disease, and frontotemporal dementia with several additional programs in preclinical development. Based in Philadelphia, PA, our company has established a strategic collaboration and licensing agreement with the renowned University of Pennsylvanias Gene Therapy Program to conduct our discovery and IND-enabling preclinical work. Through this collaboration, we have enhanced access to a broad portfolio of gene therapy candidates and future gene therapy innovations that we then pair with our deep clinical, regulatory, manufacturing and commercial expertise to rapidly advance our robust pipeline of optimized gene therapies. As we work with speed and tenacity, we are always mindful of patients who may be able to benefit from our therapies. More information is available at http://www.passagebio.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about timing and execution of anticipated milestones, including initiation of clinical trials and the availability of clinical data from such trials; our expectations about our collaborators and partners ability to execute key initiatives; our expectations about manufacturing plans and strategies; our expectations about cash runway; and the ability of our lead product candidates to treat their respective target monogenic CNS disorders. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

For further information, please contact:

Passage Bio Investors:Stuart HendersonPassage Bio267-866-0114shenderson@passagebio.com

Passage Bio Media:Mike BeyerSam Brown Inc. Healthcare Communications312-961-2502MikeBeyer@sambrown.com

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Passage Bio Announces Appointment of William Chou, M.D. as Chief Executive Officer - Yahoo Finance

Newswise PHILADELPHIAAdults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving an experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

The patients had Leber Congenital Amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers, whose findings are reported in the journal iScience, delivered AAV gene therapy, which carries the DNA of the healthy version of the gene, into the retina of one eye for each of the patients in accordance with the clinical trial protocol. Within days of being treated, each patient showed large increases, in the treated eye, of visual functions mediated by rod-type photoreceptor cells. Rod cells are extremely sensitive to light and account for most of the human capacity for low-light vision.

These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness, said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology at Penn.

LCA is one of the most common congenital blindness conditions, affecting roughly one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another but all such patients have severe visual disability from the earliest months of life. There are more than two dozen genes whose dysfunction can cause LCA.

Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the phototransduction cascadethe process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as can [now] make out objects and people in the dark.

Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy, said study co-author Artur V. Cideciyan, PhD, a research professor of Ophthalmology at Penn.

To the researchers, the results confirm that GUCY2D gene therapy to restores rod-based photoreceptor functionsand suggest that GUCY2DLCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from the therapy. The practical message is that there should be an emphasis on rod vision measurements at screening of LCA candidates and in monitoring them throughout a treatment trial.

The findings, the researchers said, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, and need only the resupply of a missing protein to start working again, more or less immediately.

The ongoing clinical trial is registered at clinicaltrials.gov as trial NCT03920007.

Support for the research was provided by Atsena Therapeutics, Inc., the developer of the GUCY2D gene therapy; the National Institutes of Health (R01 EY11522); and by a CURE Formula grant from the Pennsylvania Department of Health.

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Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness - Newswise

A protein that helps make neurons also works to reprogram scar tissue cells into heart muscle cells, especially in partnership with a second protein, according to a study led by Li Qian, PhD, at the UNC School of Medicine.

CHAPEL HILL, N.C. Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts.

In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition.

Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific.

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, said 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.

Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial 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 the new study, Qians team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings.

Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer transcription factor proteins that had been used to make the neurons.

Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming the proportion of successfully reprogrammed cells by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.

In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.

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

The results show that the major transcription factors used in direct cellular reprogramming arent necessarily exclusive to one targeted cell type.

Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them.

Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian. Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

Media contact: Mark Derewicz, 919-923-0959

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Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom - UNC Health and UNC School of Medicine

Demand for viral-vector-based gene therapies has risen to unprecedented levels, thanks to their potential to help treat previously incurable diseases. The two vectors most in the spotlight? Lentiviral (LV) vectors and adeno-associated viral (AAV) vectors due to the increased research and positive clinical results they are seeing across a wide range of applications, including cancer, heart disease, and hematologic and genetic disorders. The more drug developers look to expand this range of therapeutic areas, the greater the demand for commercial-scale development. So its important to understand not only how these two vectors can be applied to drug development, but also the capabilities required for scale-up that allows us to bring these innovative therapies to patients.

LV vectors are derived from the single-stranded RNA retrovirus HIV-1, and have been used extensively because of their ability to infect non-dividing cells, efficiently integrate into the host genome, carry large transgene loads, and allow for long-term transgene expression. They are predominantly used as delivery vehicles for introducing genetic modifications into cell therapies, such as CAR-T, and HSC gene therapies. Importantly, recent regulatory approvals and clinical successes with LV vectors are spurring even more interest among drug developers.

Lets look at the benefits of LV vectors in more detail:

However, LV vectors also present two major risks to safety.

The first is a risk of accidental exposure because HIV can self-replicate during manufacturing thanks to the lentiviruss high mutation and recombination rate.Though research shows that the risk is low, it remains a major safety concern for lab engineers and workers during development. Before using a lentiviral vector system, a risk assessment must be completed and documented. Typically, lentiviral vectors may be safely handled using either BSL-2 or BSL-2 enhanced controls, depending upon the risk assessment.

The second risk is the potential for oncogenes to occur in cells through insertional mutagenesis. For this reason, lentiviral vectors are predominantly used for cell therapy applications with genetic modification of cells ex-vivo. Only limited use is seen for direct in vivo therapies.

Unlike their LV cousins, AAV vectors are single-stranded DNA parvoviruses that can replicate only in the presence of helper viruses, such as the adenovirus, herpes virus, human papillomavirus, and vaccinia virus. Following several landmark approvals, AAV vectors are currently being used for in vitro, ex vivo, and in vivo research. AAV therapies predominantly target rare genetic disorders for which the patient population tends to be highly limited. As the market is so small, drug developers feel immense pressure to be first to market to commercialize their therapies.

The biological elements of AAV vectors make them a very attractive candidate for gene therapy for several reasons:

As with LV vectors, AAV vectors come with several drawbacks that affect their applications and efficiency.

Firstly, AAV vectors are limited by their restricted capacity for insertion of transgene DNA; because of their relatively small transgene size, they are unable to deliver genes larger than 4.8 kilobytes. Secondly, the generation of neutralizing antibodies against AAV in non-human primates (NHP) and humans may attenuate the curative effects of AAV-mediated gene therapies and limit the size of patient populations suitable for these therapies. Thirdly, there are several different serotypes and capsids for AAVs, all of which have different production and purification requirements and vary greatly with respect to function and efficacy. Fourthly, AAV drug products have varying degrees of empty and partially filled capsids, and these have implications for safety and efficacy. Generally, the highest possible percentage of AAV particles with the full transgene DNA is desired, and this varies significantly depending on the production method, AAV serotype, and the transgene itself. The latter two factors introduce significant manufacturing challenges for AAV therapies.

Overall, the industrys collective ability to successfully scale up LVV and AAV vectors faces two challenges:

i) Manufacturing each viral vector currently requires different processes, so companies cannot apply a one-size-fits-all approach to their upstream and downstream processes. Therefore, manufacturing requires immense scientific and market expertise to make the informed decisions necessary for developing a robust plan.

ii) Given the industrys limited experience with commercial-scale viral vector supply, companies need to work closely with regulatory agencies. This can be especially challenging during the transition from preclinical to commercial, where complexities arise that can cause potential delays resulting in increased costs.

As demand continues to rise, pharma companies must understand how to navigate these challenges to continue delivering their life-saving medications.

Head of Commercial Development for Viral Vector, Cell and Gene Technologies (CGT) at Lonza

She works closely with the innovation, operations, engineering, strategic marketing, and business teams to enable prioritization, strategic development and commercialization of viral vector production services for CGT. Suparnas background is in Neuroscience, and she earned her PhD in Neuropharmacology from the University of Toronto. She has over 15 years of broad pharmaceutical and CDMO experience driving innovation, drug discovery, product and service development for CNS, oncology, and cell and gene therapy.

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The Pros and Cons of Lentiviral and Adeno-Associated Viral Vectors - The Medicine Maker

This month, Insights & Outcomes digs into the nitty gritty of quantum potholes, foreign DNA, relapsing fever, and the thermodynamics of hydrogen binding.

As always, you can find more science and medicine research news on Yale News Science & Technology and Health & Medicine pages.

In some quantum mechanical systems, researchers say, the energy landscape is going to have a few potholes touching points where the state of the system is not defined. Understanding how these potholes, known as singularities, affect a quantum systems behavior is a key area of physics research.

In a new study in the journal Science, incoming Yale assistant professor of physics Charles D. Brown II and his collaborators found a new approach for probing certain types of quantum singularities.

For the study, Brown and co-authors from the University of California-Berkeley conducted a unique quantum simulation experiment with intersecting lasers that trap and manipulate ultra-cold atoms in crystals made of light. The researchers moved the atoms along trajectories that entered, turned, and exited singularities at linear touching points (called Dirac points) and quadratic touching points.

A quadratic band touching point is a point at which two energy bands have equal values but away from this point the energy values are non-equal, and the gap between the energy bands grows proportional to the square of the distance from the point.

The researchers found that the ultimate state of the system depended only on the entry and exit angles through the singularities.

We developed a distinct method to probe singularities, importantly including non-Dirac singularities, in ultracold atom quantum simulators, Brown said.

Brown is first author and co-corresponding author of the study. Dan Stamper-Kurn of the University of California-Berkeley is the senior and co-corresponding author.

Relapsing fever, a condition caused by bacterial infections transmitted by lice or tick bites, is characterized by recurrent bouts of fever, headache, and muscle aches. If left untreated, it can cause severe disability and even death.

Yet the condition which often afflicts people living in poorer regions of Africa, central Asia, and Central and South America remains a relatively unstudied disease.

In a new study, a team of Yale researchers analyzed different species of Borellia bacteria that cause many cases of relapsing fever and Lyme disease in humans, identifying a single molecule that allows two species of Borrelia to avoid immune system detection. They found that mice infected with relapsing fever but lacking the molecule CD55 had lower levels of the pathogen and a bolstered immune response.

While CD55 normally acts as a regulator of immune system response to protect potentially damaging response to host tissues, in cases of relapsing fever it is hijacked by bacteria to avoid detection and eradication, explained co-lead author Gunjan Arora, associate research scientist in the lab of senior author Erol Fikrig, the Waldemar Von Zedtwitz Professor of Medicine (Infectious Diseases) and Professor of Epidemiology (Microbial Diseases) and of Microbial Pathogenesis. The pathogens got very smart and used a molecule designed to balance our immune system response to survive in the host, Arora said.

Geoffrey Lynn, associate research scientist, is co-lead author of the study published in the journal mBio.

For decades, researchers studying the conversion of light energy into electrical or chemical energy such as in solar cells have focused on the movement of electrons, which are central to the process.

But in a new study in the journal Chem, Yale chemists James Mayer and Hyunho Noh take a different approach. They looked at energy conversion reactions as a type of whole atom transfer of hydrogen atoms, which have one electron and one proton, and are found in most energy conversion reactions.

For the study, Mayer, the Charlotte Fitch Roberts Professor of Chemistry in Yales Faculty of Arts and Sciences, and Noh, a postdoctoral associate in chemistry, measured the thermodynamics of hydrogen-atom binding to nickel oxide electrodes when in contact with three solvents: water, dimethylformamide, and acetonitrile.

Our work shows that the electron-only model is not sufficient, Mayer said. The other new approach this paper develops is that the solid/solution interface has a range of surface sites, with somewhat different strengths of chemical bonds. While this range of energies is well known in some areas of surface science, the importance of this effort has not been emphasized.

They found that the binding of hydrogen was the same no matter which solvent they used or what was dissolved in the solution, showing that this parameter is the best intrinsic property of the electrode, while the electron-only parameters vary strongly with the nature of the medium.

A medication commonly used to treat heart failure may also reduce alcohol drinking, especially among those diagnosed with alcohol use disorder, researchers from Yale School of Medicine and the National Institutes of Health Intramural Research Program (NIH IRP) report.

The effects of the drug spironolactone on drinking behavior in mice, rats, and humans were reported in the journal Molecular Psychiatry.

This is a remarkable example of bench to bedside team science showing that an inexpensive, off-patent drug, may help reduce alcohol consumption, said co-senior author Amy Justice, the C.N.H. Long Professor of Medicine and professor of public health.

In animal models of excessive alcohol drinking, researchers from the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) IRPs found that when administered to rats and mice, spironolactone reduced consumption of alcohol, and it did so in a dose dependent manner.

The Yale team, headed by Justice, then analyzed data from the U.S. Department of Veterans Affairs to assess the effects of spironolactone taken for at least 60 days on individuals reporting current alcohol use. Compared to similar individuals who did not receive the drug, those who took spironolactone reported greater decreases in alcohol consumption, the researchers found.

And those who had more severe alcohol problems, particularly those diagnosed with alcohol use disorder, benefitted the most, Justice said.

There are limited number of drugs that can help reduce harmful alcohol consumption, which costs the U.S. healthcare system $28 billion annually and another $179 billion in lost productivity, according to the Centers for Disease Control and Prevention.

Spironolactone is a medication in widespread use and a proven safety profile that is no longer on patent offering a ready additional tool to treat alcohol use disorder, the authors said.

All together, our findings provide strong justification for randomized clinical trials to further investigate the potential of this medication in patients with alcohol use disorder, said co-first author Christopher Rentsch, assistant professor at the Yale School of Medicine and London School of Hygiene & Tropical Medicine.

Lorenzo Leggio of the NIDA and NIAAA IRPs and Leandro Vendruscolo of the NIDA IRP are co-senior authors.

Yale scientist Emily Sandall will spend a year with the Office of Trade Policy & Geographic Affairs in the U.S. Department of Agriculture as a recipient of the American Association for the Advancement of Sciences Science & Technology Policy Fellowship.

Sandall is a postdoctoral researcher in the Department of Ecology and Evolutionary Biology, in Yales Faculty of Arts and Sciences.

As a fellow, she will help inform science-based policies that can be enacted throughout the U.S. government.

Sandalls research has focused primarily on insect biodiversity patterns, through geographic, morphological, and phylogenetic methods. She worked as a postdoctoral research associate in the Yale Center for Biodiversity & Global Change, where she examined global dragonfly biogeography and led a team of species experts. In her fellowship role, she will be building on her biodiversity and global change research focus and applying it to multilateral affairs in agriculture policy.

Foreign DNA, or genetic material that comes from an organism of the same or different species, is key to the survival of bacteria, helping them resist antimicrobial agents and adapt to a variety of changing environments. Bacterial pathogens also often rely on foreign genes to cause disease in humans. But how do bacteria know which foreign genes to accept?

To answer this question, researchers in the lab of Eduardo Groisman, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, zeroed in on the role of a widespread protein known to prevent the expression of foreign DNA. In doing so, they solved the question of how bacteria can overcome foreign gene silencing to access the benefits of foreign DNA.

Specifically, the researchers explored how bacteria can express genes otherwise suppressed by the foreign gene silencing protein H-NS. Because H-NS amounts were believed to remain constant, researchers had ascribed the overcoming of foreign gene silencing to other proteins. In the new study, however, Jeongjoon Choi, an associate research scientist, and Groisman found that the human pathogen Salmonella Typhimurium degrades H-NS when inside a mammalian host and they identified the enzyme responsible for H-NS degradation.

According to their findings, the researchers identified a mutant form of H-NS that resists degradation and found that the beneficial bacterium Escherichia coli cannot express foreign genes or colonize the gut of mice when it harbors the mutant H-NS.

The researchers demonstrated that H-NS degradation is essential for different bacterial species to express foreign genes, showing that beneficial E. coli and pathogenic Salmonella both use the same strategy to overcome gene silencing and thus adapt to the specific environments they face during infection. The research was published in the Proceedings of the National Academy of Sciences.

Creating new neuropsychiatric drug candidates from a virtual library

Study finds all African carnivores at risk for range loss

Yales Spielman wins $3 million Breakthrough Prize

The roots of biodiversity: how proteins differ across species

Jumping genes yield new clues to origins of neurodegenerative disease

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Insights & Outcomes: Foreign DNA, quantum potholes and relapsing fever - Yale News

Completing an investigational new drug (IND) application can be a long and tedious process, one known to bog down timelines and frustrate sponsors looking to take their cell or gene therapy (CGT) to the clinic. In a tight race to trials, program sponsors look for efficiencies from bench to bedside.

Using off-the-shelf materialssuch as plasmid DNA products and CRISPR-associated nucleases is one way to potentially speed things up particularly if they come with a drug master file, or DMF.

Drug master files are reference packages that report to the FDA information about the processes involved in new drug products. Theyre not FDA-required nor approved nor denied but they can help supplement INDs and other applications as a way to cross-reference new processes with pre-filed submissions.

And as a concept, DMFs arent new. Download the DMF list and youll see tens of thousands of submissions, some dating to 1939. Theyve always been used to support various materials, even ibuprofen and acetaminophen. But as normalized as theyve become, DMFs are still novel among CGTs, which only recently began using off-the-shelf materials that would benefit from a DMF.

With the growing standardization of cell and gene therapies, interest has emerged in DMFs as a tool to expedite the path to clinical trials. If you use an off-the-shelf reagent that has a DMF, the application links to that preexisting file without the filer having to provide redundant information.

As more off-the-shelf materials such as plasmids become available for cell and gene therapies, suppliers are submitting DMFs for those products as a benefit to customers. Doing so gives researchers a dual offering: They can not only access standardized materials at GMP-grade with the cost and time savings that come with that but they can also cross-reference their INDs to the already prepared DMF.

Two examples of these DMF-ready products are Aldevrons SpyFi Cas9 nuclease and pALD-X80 helper plasmid, each available from research grade to GMP. When new cell and gene therapy products use these materials, users automatically get the benefit of a pre-filed DMF that references Aldevrons manufacturing processes involved in making them.

The reason IND submissions have long embraced DMFs is the same reason DMFs are likely to rapidly expand among CGT applications in the months and years ahead: Theyre not just efficient in saving time, but theyre also potentially more comprehensive with less of a risk of missed information.

If you use the SpyFi Cas9 nuclease, for example, or others offered from Aldevron, you can skip the drug substance part for the Cas9 product when filing the IND because Aldevron has already prepared the DMF.

And when linking to the DMF, the FDA gets complete access to manufacturing information without the filer having to do so. This avoids overlooking information the FDA might need, which can delay application review.

Moreover, translational medicine organizations may find particular value in DMF-ready products because they overcome resource barriers inherent to hospitals and academic institutions. Unlike big pharma or biotech companies, many such organizations may not have easy access to field experts. Turning to DMFs gives academic outfits the economies of scale they might not get otherwise.

By 2025 thats just two years away the FDA expects to approve up to 20 cell and gene therapy products per year. With all that IND activity in a crowded market, sponsors will need any differentiating efficiency they can get along the pathway to clinical trials and beyond.

By taking advantage of pre-filed DMFs, researchers benefit from the value, time savings and reduced complexities of having someone else do the heavy lifting for key components of the final drug product. After all, this concept isnt new in drug development. However, the science in this so-called new frontier of medicine is. As it becomes more standardized, everyone wins including future patients.

Looking for other ways to standardize processes and accelerate your path to market? Stay tuned for Aldevrons next post, where well explore how plasmid backbones can simplify development logistics and reach your goals faster.

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Expediting IND applications with drug master files - BioPharma Dive

Led by Sam McLean, MD, MPH, University of North Carolina at Chapel Hill researchers and collaborators were awarded $3 million from the U.S. Department of Defense for to evaluate the efficacy of a therapeutic to reduce the frequency and severity of acute stress disorder and posttraumatic stress disorder.

The UNC Institute for Trauma Recovery in the UNC Department of Psychiatry has been awarded a $3-million grant from the U.S. Department of Defense (DoD) to investigate the potential of a therapeutic agent to reduce the frequency and severity of acute stress disorder and post-traumatic stress disorder (PTSD). Acute stress disorder refers to the bodys immediate response to trauma, whereas PTSD is the long-term effects of trauma.

Historically, we have been able to provide emergency care to address immediate and long-term problems after visible wounds using tools such as sutures and antibiotics. However, we still have nothing to offer trauma survivors, whether in the emergency department or on the battlefield immediately after trauma, to prevent the development of invisible wounds, said principal investigator Samuel McLean, MD, MPH, professor of psychiatry and emergency medicine and director of the Institute for Trauma Recovery at the UNC School of Medicine. We need to investigate potential treatments like ACER-801 in an effort to better address these challenges.

The proposed OASIS trial will examine the safety and efficacy of ACER-801 (osanetant) to reduce acute stress response symptoms, posttraumatic stress disorder symptoms and behavioral changes among patients presenting to the emergency department after a motor vehicle collision.

Participating sites will include Washington University in St. Louis, University of Massachusetts Chan Medical School, Rhode Island Hospital, University of Florida College of Medicine Jacksonville, and Indiana University School of Medicine. The study, proposed to begin in the first half of 2023, will evaluate the efficacy of ACER-801, which Acer Therapeutics licensed from Sanofi in 2019.

The OASIS trial builds upon a foundation of knowledge and infrastructure developed through the UNC-led, $40 million AURORA initiative. The AURORA study is a major national research initiative to improve the understanding, prevention, and recovery of individuals who have experienced a traumatic event. AURORA is supported by funding from NIH, One Mind, private foundations, and partnerships with leading tech companies such as Mindstrong Health and Verily Life Sciences, the healthcare arm of Googles parent company Alphabet.

We are proud to be partnering with a leading academic institution in the field of trauma recovery as we begin exploring ACER-801 as a treatment option to reduce the frequency and severity of acute PTSD, said Adrian Quartel, MD, FFPM, Chief Medical Officer of Acer. The data from thousands of motor vehicle collisions collected through the AURORA initiative should allow us to better predict the correlation of the emergence of acute stress disorder or PTSD symptoms following a motor vehicle collision.

Added Brandon Staglin, President of One Mind We are thrilled to see how our funding to the AURORA initiative over the last five years is accelerating further advancements such as the OASIS Trial. The targeted outcomes of the OASIS Trial are the types of results that One Mind supports and of incredible value to anyone who experiences trauma and traumatic stress.

Acute and chronic stress disorders can affect both civilian and military populations. According to the National Center for PTSD, in the US about 60% of men and 50% of women experience at least one trauma in their lives. In the United States alone, one-third of emergency department visits (40-50 million patients per year) are for evaluation after trauma exposures, and in a 2014 study involving 3,157 US veterans, 87% reported exposure to at least one potentially traumatic event during their service.3 Moreover, as many as 500,000 US troops who served in wars between 2001 and 2015 were diagnosed with PTSD.

Scientific rationale for OASIS:

TheTacr3gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, Neurokinin B (NKB), which is encoded by the Tac3 (human) gene.

The role ofNKB-NK3R in growth and reproduction has been extensively studied, butNKB-NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system. In animal models, Tac2 mRNA levels are rapidly up-regulated during fear consolidation 30 minutes after fear conditioning, and subsequent NKB-NK3R activation can lead to over stress sensitization and the consolidation of fear, and treatment with osanetant has been shown to block a critical fear/stress sensitization step in the brain. An effective therapeutic to reduce acute and persistent/long-term psychological and somatic symptoms would fulfill a large unmet need.

Media Contact: Mark Derewicz, 919-923-0959

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UNC School of Medicine Awarded $3 Million to Lead Study to Reduce PTSD Frequency, Severity | Newsroom - UNC Health and UNC School of Medicine

CARLSBAD, Calif.--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, announced today that Brian M. Culley, Lineages Chief Executive Officer, will present at the Alliance for Regenerative Medicine 2022 Cell & Gene Meeting on the Mesa, on October 12th, 2022 at 2:15pm PT / 5:15pm ET at the Park Hyatt Aviara, Carlsbad, CA. Virtual meeting attendance is available and includes a livestream of Lineages presentation and the ability to view all conference sessions on-demand. Interested parties can visit the 2022 Cell & Gene Meeting on the Mesa website for full information on the conference, including registration.

The Cell & Gene Meeting on the Mesa is the sectors foremost annual conference bringing together senior executives and top decision-makers in the industry to advance cutting-edge research into cures. Tackling the commercialization hurdles facing the cell and gene therapy sector today, this meeting covers a wide range of topics from clinical trial design to alternative payment models to scale-up and supply chain platforms for advanced therapies. The program features expert-led panels, extensive partnering capabilities, exclusive networking opportunities, and dedicated presentations by the leading publicly traded and privately held companies in the space. This conference enables key partnerships through more than 3,000 one-on-one meetings while highlighting the significant clinical and commercial progress in the field.

About the Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory, reimbursement and manufacturing initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-engineered therapies. In its 13-year history, ARM has become the global voice of the sector, representing the interests of 450+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include five allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelial cell therapy in development for the treatment of geographic atrophy secondary to age-related macular degeneration, is being developed under a worldwide collaboration with Roche and Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer; (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy; and (v) PNC1, a photoreceptor neural cell therapy for the treatment of vision loss due to photoreceptor dysfunction or damage. For more information, please visit http://www.lineagecell.com or follow the company on Twitter @LineageCell.

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Lineage to Present at Alliance for Regenerative Medicine 2022 Cell & Gene Meeting on the Mesa - businesswire.com

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The Next Crispr Gene Editing IPO Could Be Near - Henry Herald