Telomere Syndrome

Elixirgen Therapeutics is currently enrolling patients in its Phase 1/2 trial evaluating EXG-34217 in patients with telomere biology disorders at Cincinnati Children’s Hospital Medical CenterBALTIMORE, Sept. 25, 2024 (GLOBE NEWSWIRE) -- Elixirgen Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery, development and commercialization of therapies using its mRNA platforms, today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation (RPDD) to EXG-34217 for the treatment of patients with dyskeratosis congenita and related telomere biology disorders (DC/TBD). EXG-34217 is comprised of autologous CD34+ hematopoietic stem cells (HSCs) that have been treated ex vivo with EXG-001, a non-integrating, non-transmissible, temperature-sensitive Sendai virus vector encoding human ZSCAN4. The company is currently enrolling patients at Cincinnati Children’s Hospital Medical Center for a Phase 1/2 trial (NCT04211714). “We’re pleased with the FDA’s decision to grant EXG-34217 RPDD for the treatment of DC/TBD, a rare group of diseases that result in abnormally short telomeres that can lead to bone marrow failure and other serious health conditions,” said Aki Ko, chief executive officer of Elixirgen Therapeutics. “The RPDD is a recognition of the significant unmet need in this space and the potential of EXG-34217, and we look forward to working with the FDA as we continue to advance this program.” The FDA grants RPDD for serious or life-threatening diseases that affect fewer than 200,000 people in the United States and primarily affect patients less than 18 years of age. If a marketing application for EXG-34217 for the treatment of DC/TBDs is approved by the FDA, Elixirgen Therapeutics may be eligible to receive a Priority Review Voucher (PRV) that could be used to receive accelerated review of any subsequent application. About Elixirgen Therapeutics, Inc. Elixirgen Therapeutics, Inc. is a clinical-stage biotechnology company focused on the discovery, development and commercialization of therapies using its mRNA platforms and ZSCAN4 technology. The company has one ongoing (NCT04211714) and one completed (NCT04863131) Phase 1/2 clinical trial. For more information, visit ElixirgenTx.com. Forward-Looking Statements This press release may contain "forward-looking" statements. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in pharmaceutical research and development. Any forward-looking statements in this press release speak only as of the date of this press release, and Elixirgen Therapeutics undertakes no obligation to update or revise the statements in the future, even if new information becomes available. Contact Media Relations:Madelin Hawtin LifeSci Communicationsmhawtin@lifescicomms.com

Telo-seq -- a new tool -- is bringing telomere science into its modern era. Scientists can finally explore questions about the role of telomeres in aging and cancer that were not accessible with previous methods. The findings will inspire novel telomere-targeting therapeutics for aging-related diseases. Within each of our cells, long strands of DNA are folded into chromosomes and capped with protective structures called telomeres. But telomeres shorten as we age, eventually getting so whittled down that our chromosomes become exposed, and our cells die. However, the specifics of when and how this shortening occurs and whether certain chromosomes are more affected than others have been unclear -- until now. Scientists at the Salk Institute have developed a groundbreaking tool called Telo-seq, designed to revolutionize the study of telomeres in aging and disease. Compared to existing methods, which struggle to sequence whole telomeres and can only measure their average length across all chromosomes, the new technique allows researchers to determine the entire sequence and precise length of telomeres on each individual chromosome. The researchers are already using Telo-seq to reveal novel telomere dynamics in human health and disease with unprecedented resolution. The findings, published in Nature Communications on June 18, 2024, will inspire a flurry of new studies and telomere-targeting therapeutics to treat age-related diseases. "Previous methods for measuring telomere length were low resolution and rather inaccurate," says the study's senior author Jan Karlseder, professore, chief science officer, and Donald and Darlene Shiley Chair for Research on Aging at Salk. "We could hypothesize about how individual telomeres might play a role in aging and cancer, but it was simply impossible to test those hypotheses. Now we can." Karlseder and colleagues collaborated closely with experts at Oxford Nanopore Technologies to combine aspects of their long-read sequencing technique with novel biochemistry and bioinformatics approaches. The resulting method starts at the end of each telomere and sequences well into the subtelomere region. This allows the scientists to identify which chromosome they are looking at and examine its telomere structure and composition in detail. Using this technique, the researchers have described numerous features of telomere biology that had not been accessible to scientists before. So far, they've observed that within individual human samples, each chromosome arm can have different telomere lengths, and these telomeres can vary significantly in their shortening rates. These dynamics vary in different tissues and cell types within the same person, likely for many reasons including the amount of stress and inflammation affecting different parts of the body. Altogether, this suggests that there are potential chromosome arm-specific factors influencing telomere dynamics in aging and disease. "Aging is an incredibly heterogeneous process that affects everyone differently," says Karlseder. "We are very interested in whether differences in aging are related to different telomere shortening rates between people or chromosomes, and how we might be able to slow this down to promote healthy aging." Telo-seq can also improve our understanding of telomere-driven diseases. Many telomeropathies involve stem cells that run out of telomere length and lose their ability to divide into new, functional cells. This can lead to hair loss, immune disorders, or certain cancers. Telo-seq will allow scientists to investigate whether these diseases are inherited within families or associated with individual chromosomes, in order to develop more targeted interventions. While telomere shortening can have devastating effects on a cell's lifespan, the opposite scenario can be equally damaging. When telomere repair mechanisms are overactivated, cells can enter an "immortal" state and divide indefinitely, leading to cancer. To repair a damaged telomere, cells can either use the telomerase enzyme or another mechanism known as the alternative lengthening of telomeres (ALT). The length and composition of the telomeres will differ depending on which maintenance mechanism was used but, until now, there was no efficient way for scientists or clinicians to measure this. "With Telo-seq, we can quickly determine whether a cancer is telomerase-positive or ALT-positive," says first author Tobias Schmidt, a postdoctoral researcher in Karlseder's lab. "This is critical because ALT-positive cancers are often more aggressive and require different treatment approaches than telomerase-positive cancers. In this sense, Telo-seq could be used as a quick and reliable diagnostic tool to identify cancer types and guide more personalized treatment plans." Beyond its many immediate clinical applications, Karlseder and Schmidt say Telo-seq's greatest impact will be in igniting a new era of telomere research. "Telo-seq will allow us to answer questions about development, aging, stem cells, and cancer that we simply couldn't address with previous tools," says Karsleder. "We don't even know what we've been missing, and I think the things we're starting to learn now are really just the tip of the iceberg. It's a very exciting time for telomere science." Other authors include Candy Haggblom, Jeffrey R. Jones, and Fred H. Gage of Salk, Kelly A. Frazer of UC San Diego, and Carly Tyer, Preeyesh Rughan, Xiaoguang Dai, Sissel Juul, and Scott Hickey of Oxford Nanopore Technologies, Inc. This work was supported by the National Institute of Aging (P30AG068635, AG0773424), the National Cancer Institute (CA227934, CA234047, P30CA014195), the National Institute for General Medicine (GM142173), the Helmsley Charitable Trust, the Shiley-Marcos Alzheimer's Disease Research Center at UC San Diego (AG062429), the European Molecular Biology Organization (ALTF 668-2019), the JBP Foundation (#2021-2961), the Paul F. Glenn Center for Biology of Aging Research at Salk Institute, and an AHA-Allen Initiative in Brain Health and Cognitive Impairment award made jointly through the American Heart Association and The Paul G. Allen Frontiers Group (19PABH134610000).

New findings describe how the enzyme CST is recruited to the end of the telomere, where it maintains telomere length with the help of subtle chemical changes made to the protein POT1. The length of telomeres that protect the ends of our chromosomes should be tightly regulated. Those that are too long predispose to cancer, and those that are too short lose their protective ability, resulting in telomere disorders with serious health consequences. Our cells prevent this excessive shortening by adding telomeric DNA to the ends of chromosomes. Researchers at Rockefeller recently showed that this process is mediated by two enzymes: telomerase and the CST-Polα/primase complex. Having determined how telomerase is recruited, scientists were left with a fundamental question: how does CST-Polα/primase find its way to the telomere? Now, a new study published in Cell demonstrates that CST is recruited to the end of the telomere and regulated by subtle chemical changes made to POT1, a protein in the shelterin complex involved in telomere maintenance and implicated in cancer risk. The findings provide new insight into how human telomeres function at the molecular level, with implications for numerous diseases and disorders. "After the discovery of telomerase, it took decades to figure out how it gets to the telomere. Now, just months after discovering that CST-Polα/primase is the second critical enzyme required for telomere maintenance, we understand the details of how it is recruited," says Titia de Lange, the Leon Hess professor. "Moreover, we've found out how this process is regulated." Recruiting and regulating CST Telomeres have two different types of strands, G-rich and C-rich. Scientists have long known how telomerase maintains the length of the G-rich strand, but only recently was it recognized that the same problem also exists for the C-rich strand. A recent study from the de Lange lab identified the CST-Polα/primase complex as the key regulator responsible for keeping that strand intact. What remained to be seen was how CST, and its associated enzyme Polα-primase, travels to telomere to facilitate C-strand maintenance across replication cycles. Sarah Cai, a PhD candidate at Rockefeller, began investigating this piece of the telomere puzzle. Building on a decade of the de Lange lab's groundwork on CST, Cai added cryo-EM to the techniques used in this study while being co-advised by Rockefeller's Thomas Walz. "The interdisciplinary nature of the study is one of the most exciting parts," Cai says. "It was a very successful double-lab effort, making use of many different technologies." Walz, whose research focuses on cryo-EM, noted how Cai incorporated AlphaFold, a deep-learning algorithm that can predict the unique 3D structures of proteins, into her work. With the combined power of biochemistry, structural biology, and cell biology, the team ultimately confirmed that CST is recruited to telomeres by the POT1 protein. Once CST-Polα/primase is onsite, the addition and removal of phosphate groups from POT1 appears to function as an on/off switch that coordinates the final steps of telomere replication. Phosphorylated POT1 ensures that CST-Polα/primase remains inactive until telomerase has finished its job, upon which the dephosphorylation of POT1 activates CST-Polα/primase to add the finishing touches to the telomere. Telomere disorders and cancer Next, the team will look for specific enzymes that attach and remove phosphates during this process, controlling the on/off switch on POT1, and determining their role in regulating CST-Polα/primase recruitment and activity. A better understanding of how CST is recruited to the telomere cannot come fast enough for patients suffering from telomere disorders, such as Coats plus syndrome, a severe multi-organ disease characterized by abnormalities in the eyes, brain, bones, and GI tract. "For a long time, we didn't know why mild alterations in single amino acids would cause such a devastating disease," Cai says. "We now have a better idea of how these mutations affect the recruitment of this critical telomere maintenance machine and lead to Coats plus syndrome." The findings will also impact their cancer research. The de Lange lab has spent decades studying how telomere shortening contributes to tumor suppression and genome instability in cancer, and the present research may ultimately help answer questions that lie at the heart of tumor development. "Anything critical to telomere length regulation may well be critical to cancer prevention too," de Lange says. "This is a major focus of our lab, and one of the reasons we'll be looking into the interplay between CST-Polα/primase and telomerase more closely in the future."