Long-Lasting Gene Therapy Benefits Advanced Heart Failure Patients
Cardiovascular Research Center at Mount Sinai report promising long-term follow-up results for its single dose AAV1/SERCA2a gene therapy in advanced heart failure patients.
Researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai reported the long-term benefits of a single dose of their gene therapy AAV1/SERCA2a in advanced heart failure patients on Nov. 19 at the American Heart Association Scientific Sessions 2013.
The new long-term follow-up results from their initial Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) clinical trial found a one-time, high-dose injection of the AAV1/SERCA2a gene therapy results in the presence of the delivered SERCA2a gene up to 31 months in the cardiac tissue of heart failure patients.
In addition, study results show clinical event rates in gene therapy patients are significantly lower three years later compared to those patients receiving placebo. Also, patients experienced no negative side effects following gene therapy delivery at three-year follow-up.
"This study shows AAV1/SERCA2a gene therapy has long-lasting and beneficial effects for congestive heart failure patients allowing us to block the downward spiral of patients with severe heart failure, ” says principal investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine at Icahn School of Medicine at Mount Sinai, who developed the gene therapy approach.
The gene therapy uses a modified adeno-associated viral-vector derived from a parvovirus. The one-time gene therapy is injected through the coronary arteries of heart failure patients using catheters. It works by introducing healthy SERCA2a genes into cells. The delivery of the SERCA2a gene produces SERCA2a enzymes, which helps heart cells restore their proper use of calcium.
SERCA2a is an enzyme critical for proper pumping of calcium in calcium compartments within cells. SERCA2a dysfunction or reduced expression occurs in patients with heart failure. When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. This contributes to an enlarged heart in heart failure patients.
Previously, CUPID 1 study results showed the gene therapy to be clinically safe and effective for over 12 months with improved heart function status and left ventricular function, along with a significant decrease in recurrent cardiovascular events. CUPID 1 was the first-in human clinical gene therapy randomized, double-blind study which enrolled 39 patients with advanced heart failure.
"AAV1/SERCA2a gene therapy has been proven to be a safe and effective therapeutic intervention for advanced heart failure,” says Dr. Hajjar. "Our long-term results support the potential use of AAV1/SERCA2a gene therapy as a new important additional tool for treating and managing advanced heart failure patients.”
This study was presented as an Oral Session (Abstract 10667): Long Term Follow-up of Patients with Advanced Heart Failure Following a Single Intracoronary Infusion of AAV1/SERCA2a.
In addition, on Nov. 19 Dr. Hajjar also presented at the AHA Scientific Sessions 2013 a Plenary talk entitled, "How the Postgenome Era Will Change the Practice of Cardiology” and discussed his work on targeted gene therapy for human heart failure.
In his Plenary talk, Dr Hajjar presented his new findings just published in the journal Science Translational Medicine on Nov. 13 that show delivery of small ubiquitin-related modifier 1 (SUMO-1), an important regulator of SERCA2a, in preclinical heart failure models improves cardiac contractility and prevents left ventricular dilatation — two major aspects of heart failure. According to Dr. Hajjar, the transition of this SUMO-1 gene therapy from pigs to humans seems likely in the short-term. Also, Dr. Hajjar revealed that development of novel cardiotropic vectors may render cardiovascular gene therapy easier and less-invasive in the near future.
Dr. Hajjar is the scientific cofounder of the company Celladon, which is developing AAV1/SERCA2a gene therapy for the treatment of heart failure. He holds equity in Celladon and receives financial compensation as a member of its advisory board.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology, Mount Sinai St. Lukes and Mount Sinai West are ranked 23rd nationally for Nephrology and 25th for Diabetes/Endocrinology, and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.