Development of Novel Cardiac Myocyte-Specific AAV Capsids
Abstract
Gene therapies are biologic drugs that delivery a custom synthetic gene to cells of the body, fixing a genetic defect or introducing a new gene that confers benefit in disease. The development of gene therapy drugs is one of the most exciting areas of modern drug development. In particular, with the approval by the U.S. Food and Drug Administration of gene therapy drugs for the eye diseases Leber congenital amaurosis and retinitis pigmentosa and for the muscular disease spinal muscular atrophy, new gene therapies are actively being sought for many chronic diseases, including those affecting the heart. Gene therapies are being proposed for all types of heart diseases, including for inherited diseases like cardiomyopathy that occur in families and for common acquired diseases like heart attacks (myocardial infarction) and heart failure. These gene therapies typically take the form of synthetic adeno-associated viruses (AAV). AAV are small viruses that are useful as biologic drugs. AAV naturally present in the environment do not cause disease and are readily modified to deliver a synthetic mini-gene that might alter cells in a beneficial way in disease. In theory, AAV constitute an almost limitless approach to correcting diseased cells by altering their gene program. In this project, we address within the Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Portfolio – Cardiovascular Health, the FY22 PRMRP Topic Area – Cardiomyopathy, and the FY22 PRMRP Strategic Goal – Develop novel therapeutics or advance treatment regimens for associated cardiovascular conditions that address sex/gender or ethnic/racial differences. A major problem for the field of cardiac gene therapy is the lack of AAV that treats only the heart. Current AAV biologics will disperse throughout the body, delivering their genetic cargo to many different types of cells that are not intended to be treated and where the gene therapy can have deleterious side effects. The heart comprises about 1/200th of the body by weight, and as most AAV drugs end up elsewhere, much larger doses of drug must be used to treat the heart. Besides the obvious need to manufacture large amounts of drug to get at least some to the heart, infusion of large doses of AAV can make the patient ill through activation of the immune system. This has resulted in paused clinical trials. In this project, we propose to take a novel approach to the design of AAV gene therapy vectors to discover an AAV that would deliver its cargo uniquely to the heart. In this PRMRP Discovery Award, we will identify novel AAV that may be used to design gene therapies for heart disease. An immediate application will be the rescue of genetic defects in familial cardiomyopathies. In mouse models for cardiomyopathy, it has been shown that a mutant gene causing disease can be replaced with a properly functioning gene by delivering the normal gene to the heart using AAV. For multiple technical reasons, however, AAV useful in mice for heart disease are not easily deployed in human patients. The key milestone to solving this problem for human patients will be to acquire an AAV that will efficiently carry the normal gene to the patient’s heart and nowhere else in the body. Successful completion of this project will result in the development of a new AAV that has the potential to transform gene therapy for human heart disease, including cardiomyopathy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310057
Entities
People
- Michael S Kapiloff
Organizations
- Stanford University
- United States Army