PPIF

Researchers have discovered that the enzyme cyclophilin A, which is produced in large amounts in hematopoietic stem cells, is key for these cells to retain their regenerative potential and avert the effects of aging via an unexpected mechanism. Nothing lives forever, but compared to other cells in the body, hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs are blood-forming cells -- they give rise to rapidly dividing progenitor cells, which in turn generate hundreds of billions of cells to fulfill the daily demand of oxygen-delivering red blood cells, disease-fighting white blood cells and clot-forming platelets. HSCs typically remain dormant within the bone marrow, yet they possess the ability to activate and replenish blood cells continuously, maintaining a relatively youthful pro the life of an organism. What is the secret of long-lived HSCs that wards off the effects of aging? A team led by researchers at Baylor College of Medicine revealed in Nature Cell Biology that the enzyme cyclophilin A, which is produced in large amounts in HSCs, is key for these cells to retain their regenerative potential and avert the effects of aging. Long live the stem cells! "A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life," said corresponding author Dr. André Catic, assistant professor and CPRIT Scholar in Cancer Research in the Huffington Center on Aging at Baylor. "With age, proteins tend to misfold, aggregate and accumulate inside the cell, which leads to toxic stress that can disrupt cell function." Cells that frequently engage in cell division, like progenitor cells, can dispose of protein aggregates through dilution. On the other hand, long-lived HSCs, which do not divide often, face the problem of the accumulation of misfolded proteins and subsequent toxic stress. Nevertheless, HSCs remain impervious to aging. How do they do it? "Understanding the molecular mechanisms that contribute to HSC aging not only contributes to the field of normal HSC biology, but also may have significant clinical relevance for cancer treatment," said co-first author of the work, Dr. Lauren Maneix, who was at the Catic lab while working on this project. Molecular chaperones at work Previous studies have shown that mammalian cells express several hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilins, one of the most abundant chaperones, have been implicated in the aging process. However, how they affect cellular proteins has not previously been studied. Working with mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a prevalent chaperone. Further experiments showed that the expression of cyclophilin A was significantly decreased in aged HSCs, and genetically eliminating cyclophilin A accelerated natural aging in the stem cell compartment. In contrast, reintroducing cyclophilin A into aged HSCs enhanced their function. Together, these findings support cyclophilin A as a key factor in the longevity of HSCs. Connecting cyclophilin A, intrinsically disordered proteins and HSC longevity Next, the team investigated the proteins with which cyclophilin A interacts, preserving their stability. "We found that proteins enriched in intrinsically disordered regions are frequent targets of the chaperone," Catic said. Intrinsically disordered proteins naturally change their 3-D conformation to interact with different proteins, nucleic acids or other molecules. Consequently, proteins rich in intrinsically disordered regions regulate many cellular processes by promoting specific activities between molecules. "Due to their flexible nature, intrinsically disordered proteins are inherently prone to aggregation. Cyclophilin A supports these proteins in fulfilling their functions and simultaneously prevents them from clumping," Catic said. Furthermore, the findings suggest that cyclophilin A interacts with intrinsically disordered proteins from the moment of their synthesis. "As these proteins are being made, cyclophilin A makes sure they keep the appropriate conformations and are maintained at sufficient levels," Catic said. "Genetic depletion of cyclophilin A results in stem cells distinctively lacking intrinsically disordered proteins." "For the first time, our study showed that producing disordered proteins and maintaining the structural diversity of the proteins in a cell plays a role in HSC aging," Maneix said. Co-first author Polina Iakova, Charles G. Lee, Shannon E. Moree, Xuan Lu, Gandhar K. Datar, Cedric T. Hill, Eric Spooner, Jordon C. K. King, David B. Sykes, Borja Saez, Bruno Di Stefano, Xi Chen, Daniela S. Krause, Ergun Sahin, Francis T. F. Tsai, Margaret A. Goodell, Bradford C. Berk and David T. Scadden also contributed to this study.

Hepion Pharmaceuticals’ shares lost a third of their value after the company decided to halt its mid-stage programme for rencofilstat in metabolic dysfunction-associated steatohepatitis (MASH) due to financial constraints. The drugmaker will seek strategic alternatives to pursue further development of the cyclophilin inhibitor.The Phase IIb ASCEND-NASH study kicked off in August 2022 and planned to investigate the safety and efficacy of rencofilstat versus placebo over 12 months in 336 participants. However, enrolment was stopped in April last year after 150 people were randomised. Hepion noted that nearly 80 participants had currently completed the one-year follow-up, with an additional 40 lined up for safety assessments.“Given the number of enrolled [MASH] patients to date and the low probability of generating relevant efficacy data to support a registrational trial with our current cash resources, we have opted to wind down the programme,” explained Hepion’s executive chairman John Brancaccio. He confirmed there were no safety issues associated with the drug in the study.Hepion had earlier announced a restructuring plan to preserve capital by slashing operating costs by approximately 60%, thus extending its cash runway into the second quarter of 2025. Several players, including big pharmas such as Eli Lilly and Novo Nordisk, are battling it out in the competitive MASH arena. However, the MASH debutant crown was snatched by Madrigal after clinching FDA approval for Rezdiffra (resmetirom) last month (for related analysis, read KOL Views Q&A: Leading endocrinologist lays out challenges ahead as Madrigal launches Rezdiffra in MASH).

EDISON, N.J., April 19, 2024 (GLOBE NEWSWIRE) -- Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage biopharmaceutical company that has been developing a treatment for non-alcoholic steatohepatitis (“NASH”), hepatocellular carcinoma (“HCC”), and other chronic liver diseases, today announced that it has begun wind-down activities in its ASCEND-NASH Trial, while continuing to explore strategic alternatives, as previously announced in December 2023. ASCEND-NASH is a Phase 2b, randomized, multi-center, double-blinded study with first patient screened in August 2022, to evaluate the safety and efficacy of rencofilstat dosed for 12 months, with a target enrollment of 336 subjects. Enrollment was paused in April 2023, with 151 subjects randomized. To date, approximately 80 subjects have completed their Day 365 visits and are evaluable for both safety and efficacy. An additional 40 subjects will provide significant safety data for evaluation. These patients will be added to our existing safety database. “We are disappointed to announce the wind-down of our Phase 2 NASH trial, which we attribute entirely to resource constraints,” said John Brancaccio, Executive Chairman of Hepion. “The Company remains committed to its strategic alternative efforts previously announced in December 2023. Given the number of enrolled NASH patients to date and the low probability of generating relevant efficacy data to support a registrational trial with our current cash resources, we have opted to wind down the program and assure that patients are transitioned out of the trial in a safe and compliant manner. There were no safety concerns observed for rencofilstat in the ASCEND-NASH trial.” About Hepion Pharmaceuticals Rencofilstat, is a potent inhibitor of cyclophilins, which are involved in many disease processes. Rencofilstat has been shown to reduce liver fibrosis and hepatocellular carcinoma tumor burden in experimental disease models. In November 2021, the U.S. Food and Drug Administration (“FDA”) granted Fast Track designation for rencofilstat for the treatment of NASH. That was followed in June 2022 by the FDA’s granting of Orphan Drug designation to rencofilstat for the treatment of HCC. Hepion has created and maintains a proprietary Artificial Intelligence deep machine learning (“AI/ML”) platform designed to better understand disease processes and identify patients that are rencofilstat responders. This AI/ML has the potential to shorten development timelines and increase the observable differences between placebo and treatment groups. In addition, Hepion’s AI/ML can be used to further NASH and HCC clinical development programs and identify other potential therapeutic indications for cyclophilin inhibition with rencofilstat. Forward-Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimated,” and “intend,” among others. These forward-looking statements are based on Hepion Pharmaceuticals’ current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, substantial competition; our ability to continue as a going concern; our need for additional financing; uncertainties of patent protection and litigation; risks associated with delays, increased costs and funding shortages caused by the COVID-19 pandemic; uncertainties with respect to lengthy and expensive clinical trials, that results of earlier studies and trials may not be predictive of future trial results; uncertainties of government or third party payer reimbursement; limited sales and marketing efforts and dependence upon third parties; and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. As with any drug candidates under development, there are significant risks in the development, regulatory approval, and commercialization of new products. There are no guarantees that future clinical trials discussed in this press release will be completed or successful, or that any product will receive regulatory approval for any indication or prove to be commercially successful. Hepion Pharmaceuticals does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in Hepion Pharmaceuticals’ Form 10-K for the year ended December 31, 2023, and other periodic reports filed with the Securities and Exchange Commission. For further information, please contact: Hepion Pharmaceuticals 732-902-4000 info@hepionpharma.com