Novel Gene Therapy Works to Reverse Heart Failure

Researchers have effectively evaluated a powerful gene therapy, delivered directly into the heart, designed to reverse heart failure in large animal models. Only a one-time gene therapy dose was found to be needed to restore healthy gene production of a beneficial enzyme.

Published in November 13, 2013, issue of the journal Science Translational Medicine, the study findings, is the last study phase before human clinical trials can start assessing SUMO-1 (small ubiquitin-related modifier) gene therapy. SUMO-1 is a gene that is absent in heart failure patients. “SUMO-1 gene therapy may be one of the first treatments that can actually shrink enlarged hearts and significantly improve a damaged heart’s life-sustaining function,” stated the study’s senior investigator Roger J. Hajjar, M.D., director of the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai (New York, NY, USA) and a professor of medicine at Mount Sinai. “We are very eager to test this gene therapy in our patients suffering from severe heart failure.”


Dr. Hajjar’s work is on its way toward approval from the US Food and Drug Administration (FDA) to evaluate the SUMO-1 gene therapy in heart failure patients. When it begins, the clinical trial will be the second gene therapy treatment designed to reverse heart failure launched by Dr. Hajjar and his Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

The first trial, named CUPID, is in its final phases of testing SERCA2 gene therapy. Adeno-associated virus (AAV) vectors are delivered through the coronary arteries of the failing heart during a cardiac catheterization procedure, delivering SUMO1, which then enhances the activity of a gene known as SERCA2a (sarcoplasmic reticulum calcium ATPase 2a). Phase 1 and phase 2a trial findings were positive, demonstrating considerable improvement in clinical events. In that trial, SERCA2 is delivered by way of an inert virus--a modified virus without infectious particles. SERCA2 is a gene that produces an enzyme vital to the effective pumping of calcium out of cells. In heart failure, SERCA2 is dysfunctional, forcing the heart to work harder and in the process, to grow larger.

Earlier research, however, by Mount Sinai scientists demonstrated SERCA2 is not the only enzyme that is missing in heart failure processes. A study published in the journal Nature in 2011 by Dr. Hajjar and his coworkers revealed that the SUMO-1 gene is also reduced in failing human hearts. But SUMO-1 controls SERCA2a’s activity, suggesting that it can enhance the function of SERCA2a without changing its levels. A follow-up study in a mouse model of heart failure demonstrated that SUMO-1 gene therapy substantially improved cardiac function.

This new study evaluated delivery of SUMO-1 gene therapy alone, SERCA2 gene therapy alone, and a combination of SUMO-1 and SERCA2. In large animal models of heart failure, the researchers found that gene therapy delivery of high dose SUMO-1 alone, as well as SUMO-1 and SERCA2 together, result in better blood flow, stronger heart contractions, and reduced heart volumes, compared to just SERCA2 gene therapy by itself. “These new study findings support the critical role SUMO-1 plays for SERCA2 function, and underlie the therapeutic potential of SUMO-1 gene replacement therapy for heart failure patients,” reported Dr. Hajjar.

Furthermore, according to Dr. Hajjar, the time it took investigators to convert their basic laboratory findings to successful preclinical studies was very short. “The key reason for this translational medicine speed is the outstanding infrastructure we have in the Cardiovascular Research Center at Mount Sinai, where we are able to replicate human heart failure models to test our novel gene therapies,” noted Dr. Hajjar. “I think this is a really very unique example of rapid translation of a promising medical therapy from an initial discovery to preclinical trials.”

Dr. Hajjar is the scientific cofounder of the company Celladon (San Diego, CA, USA), which plans to develop AAV.SERCA2a gene therapy for the treatment of heart failure.

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