HARS

Conference hosted by the International Union of Biochemistry and Molecular Biology (IUBMB) to feature leading research in tRNA synthetase biology. Presentations showcase company’s progress in generating new therapeutics from tRNA synthetase platform. SAN DIEGO, June 06, 2023 (GLOBE NEWSWIRE) -- aTyr Pharma, Inc. (Nasdaq: LIFE), a clinical stage biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform, today announced multiple presentations at the International Union of Biochemistry and Molecular Biology’s 13th International Symposium of Aminoacyl-tRNA Synthetases (AARS 2023), which is scheduled to take place June 4 – 9 in Ontario, Canada. “As a leader in the field of tRNA biology, we look forward to highlighting some of the recent findings from our platform at AARS 2023,” said Leslie A. Nangle, Ph.D., Vice President, Research at aTyr. “In these presentations we describe the process from concept to clinical proof-of-concept for efzofitimod, our lead tRNA synthetase-derived candidate in development for interstitial lung disease, and how we have applied that same process to identify extracellular targets for two additional tRNA synthetase candidates from our platform. Furthermore, we present exciting findings that solidify a connection between patients with certain genetic conditions and lower circulating levels of the tRNA synthetase HARS, which forms the active portion of efzofitimod. As these patients exhibit dysregulated respiratory immune responses, this data provides rationale for a link between human extracellular HARS deficiency and diseases with respiratory symptoms.” Extracellular tRNA synthetases represent a class of proteins that may play important roles in regulating cellular responses to certain disease states, in particular, cellular stress and imbalances in tissue homeostasis. aTyr is focused on elucidating novel pathways mediated through extracellular tRNA synthetases and creating new biologics to modulate these pathways by developing protein therapies based on extracellular tRNA synthetase fragments. Details of the presentations appear below. The posters will be available on the aTyr website once presented. Title: Clinical Proof-of-Concept for a Novel Therapeutic Based on Histidyl-tRNA Synthetase for Treatment of Interstitial Lung DiseasesFormat: PresentationPresenter: Leslie A. Nangle, Ph.D.Date and Time: Tuesday, June 6, 2023, at 3:30 p.m. Title: Identification of Key Fibrotic Extracellular Targets for Alanyl- and Aspartyl-tRNA Synthetases Format: Poster PresentationDate and Time: Tuesday, June 6, 2023, at 8:10 p.m. Title: Circulating His-tRNA Synthetase is Reduced in Patients Harboring the Usher Syndrome Type 3B-Linked Mutation Y454SFormat: Poster PresentationDate and Time: Tuesday, June 6, 2023, at 8:10 p.m. Title: tRNA Biology Industry Panel Format: PanelPanelist: Leslie A. Nangle, Ph.D.Date and Time: Wednesday, June 7, 2023, at 11:40 a.m. About Efzofitimod aTyr is developing efzofitimod as a potential therapeutic for patients with fibrotic lung disease. Efzofitimod, a fusion protein comprised of the immunomodulatory domain of histidyl-tRNA synthetase fused to the FC region of a human antibody, is a selective modulator of neuropilin-2 that downregulates innate and adaptive immune response in inflammatory disease states. aTyr’s lead indication for efzofitimod is pulmonary sarcoidosis, a major form of interstitial lung disease. Clinical proof-of-concept for efzofitimod was recently established in a Phase 1b/2a multiple-ascending dose, placebo-controlled study of efzofitimod in patients with pulmonary sarcoidosis, which demonstrated safety and a consistent dose response and trends of benefit of efzofitimod compared to placebo on key efficacy endpoints, including steroid reduction, lung function, clinical symptoms and inflammatory biomarkers. aTyr is currently conducting EFZO-FIT™, a global pivotal Phase 3 study of efzofitimod in pulmonary sarcoidosis. About aTyr aTyr is a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform. aTyr’s research and development efforts are concentrated on a newly discovered area of biology, the extracellular functionality and signaling pathways of tRNA synthetases. aTyr has built a global intellectual property estate directed to a potential pipeline of protein compositions derived from 20 tRNA synthetase genes and their extracellular targets. aTyr’s primary focus is efzofitimod, a clinical-stage product candidate which binds to the neuropilin-2 receptor and is designed to downregulate immune engagement in fibrotic lung disease. For more information, please visit http://www.atyrpharma.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are usually identified by the use of words such as “believes,” “expects,” “intends,” “may,” “plans,” “forward,” “potential,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by such safe harbor provisions for forward-looking statements and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements include, among others, statements regarding potential therapeutic benefits and applications of efzofitimod and research and development activities related to future tRNA synthetase candidates. These forward-looking statements also reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by these forward-looking statements, are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. Furthermore, actual results may differ materially from those described in these forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, uncertainty regarding geopolitical and macroeconomic events, risks associated with the discovery, development and regulation of our product candidates, the risk that we or our partners may cease or delay preclinical or clinical development activities for any of our existing or future product candidates for a variety of reasons (including difficulties or delays in patient enrollment in planned clinical trials), the possibility that existing collaborations could be terminated early, and the risk that we may not be able to raise the additional funding required for our business and product development plans, as well as those risks set forth in our most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and in our subsequent SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Contact:Ashlee DunstonDirector, Investor Relations and Corporate Communicationsadunston@atyrpharma.com

Large structural changes to the genomes of human ancestors could have spurred the smaller changes that set human brains apart from other primates SAN FRANCISCO, April 28, 2023 /PRNewswire/ -- More than a million years ago, large chunks of the human genome were rearranged—a chance event during egg or sperm formation that led to the deletion, duplication, or reversal of sections of DNA. Those structural variants, researchers have now discovered, likely set off a cascade of other rapid changes in human DNA that may underlie uniquely human features, particularly the brain. The new finding, published today in Science by researchers at Gladstone Institutes, came out of a study analyzing how stretches of DNA called human accelerated regions (HARs) differ between humans and chimpanzees. HARs are nearly identical among all humans, but differ between humans and all other mammals. Researchers have long wondered why these sequences—many of which control brain development—changed so rapidly in early human evolution. "What we found is that many HARs are in regions of DNA where structural variants caused the genome to fold differently in humans compared to other primates," says Katie Pollard, PhD, director of the Gladstone Institute of Data Science and Biotechnology and lead author of the new study. "This gave us an idea how HARs could have arisen in the first place." Folding like Origami When comparing human and chimpanzee genomes nearly two decades ago, Pollard discovered regions of DNA—now called HARs—that were stable in mammals for millennia, but suddenly changed in early humans. Her lab has since shown that most HARs are enhancers, short stretches of DNA that regulate the activity of genes related to brain development. But researchers still have many questions about how HARs came about and the role they play in making humans distinct from other primates. Pollard and her colleagues wondered whether other changes to the DNA surrounding HARs might help explain their origin. In collaboration with The Zoonomia Project, an international collaboration to study mammalian genomes, the researchers analyzed HARs and their surroundings in 241 mammalian genomes. They concluded that HARs tend to be located in areas of the human genome that have large structural differences when compared to other mammals. So, the scientists next probed whether the structural variations around HARs might have changed the way the DNA folded. "The way the genome folds up in three-dimensional space like origami is particularly important for enhancers," explains Pollard, who is also a professor at UC San Francisco and a Chan Zuckerberg Biohub investigator. "That's because enhancers can impact the activity of any gene that ends up close by, which can vary depending on how DNA is folded." To study the relationship between HARs and DNA folding, Pollard's team used a machine learning model they previously developed to predict DNA folding patterns, and applied it to human and chimpanzee DNA sequences. Then, they identified the regions of the genome that folded differently in humans. The computer predicted that nearly 30 percent of HARs were in areas of the genome that folded differently in humans compared to chimpanzees. "We realized that these human-specific structural changes may have created the right environment for HARs to evolve fast in the human ancestor, after remaining almost the same over millions of years of mammal evolution," said Kathleen Keough, PhD, first author of the study and former postdoctoral scholar in the Pollard lab at Gladstone. Piecing Together the Past If DNA near HARs folded differently in humans and brought different genes in proximity to HARs, this could have had drastic consequences for our ancestors. "Imagine you're an enhancer controlling blood hormone levels, and then the DNA folds in a new way and suddenly, you're sitting next to a neurotransmitter gene and need to regulate chemical levels in the brain instead of in the blood," says Pollard. "Your instructions are now out-of-date and need to be changed." The predictions from the machine learning model suggested that large structural changes had occurred near HARs, but did not demonstrate which genes had fallen under their control. To address that question, Pollard and her colleagues carried out lab experiments that let them determine, in human and chimpanzee brain cells they derived from stem cells, what stretches of DNA were closest to hundreds of different HARs. In many cases, they found, the human HARs were close to genes known to play a role in brain development; in some instances, the nearby genes were also associated with neurodevelopmental or psychiatric diseases. Pollard's team recently reported that the variations that rapidly appeared in HARs during early human evolution often opposed each other, first turning up the activity of an enhancer and then turning it down, or vice versa. The new results, she says, fit in well with the model proposed in that study. "Something big happens like this massive change in genome folding, and our cells have to quickly fix it to avoid an evolutionary disadvantage," said Pollard. "But the fix might kind of overdo it and need to be refined over time." While the new paper helps answer how HARs may have emerged in the beginning, Pollard's team still has questions they plan to follow up on about why the massive structural changes survived the test of time and how HARs impact human brain development. About the Study The paper "Three-dimensional genome rewiring in loci with human accelerated regions" was published in the journal Science on April 28, 2023. Other authors are Sean Whalen and Pawel Przytycki of Gladstone; Fumitaka Inoue, Tyler Fair, Chengyu Deng, Marilyn Steyert, Hane Ryu, Tomasz Nowakowski, Nadav Ahituv, and Alex Pollen of UCSF; and Kerstin Lindblad-Toh and Elinor Karlsson of Broad Institute of Harvard and MIT. The work was supported by a UCSF Discovery Fellowship, the National Institutes of Health (GR-01125, DP2MH122400-01, NHGRI R01HG008742), the National Institute of Mental Health (R01MH109907, U01MH116438), the Schmidt Futures Foundation, the Shurl and Kay Curci Foundation, and a Swedish Research Council Distinguished Professor Award. About Gladstone Institutes Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds. Media Contact: Julie Langelier | Associate Director, Communications | julie.langelier@gladstone.org | 415.734.5000 View original content to download multimedia: SOURCE Gladstone Institutes