Gene Therapy Improves Heart Muscle Function to Compensate for Heart Failure

Some of the changes that occur in cells and tissues in heart failure center around a progressive loss of function in the ability of heart muscle to contract. Over the past decade or so, researchers have identified increased protein phosphatase-1 (PP1) as one of the regulatory mechanisms of interest in heart muscle contraction. The inhibitor-1 (I-1) protein acts to reduce levels of PP1 via a complicated network of interactions that researchers have mapped out piece by piece over the years, making it a potential target for interventions. There are a few good open access papers out there to provide an overview of this set of biochemical relationships and its relevance to heart failure.

Given a target, there are a number of ways in which the research community can proceed: manufacturing and delivering more of the protein, for example, or searching for a drug that has the effect of increasing gene expression of the desired protein. Both of these have their limitations. These days gene therapy is becoming an ever more viable option for the development of clinical therapies, as cost decreases and reliability improves in the technologies of delivery. In principle, gene therapy has the potential to be far more accurate and targeted than other approaches. In the research results noted here, a fairly well-proven method of gene therapy is applied to reduce PP1 levels in order to improve heart muscle function in pigs. This largely repeats work from three years ago - an example of the glacial pace at which research often progresses in the later stages of animal trials.

Many of the potential gene therapy approaches to the aging heart involve spurring greater stem cell activity: to in some way capture a part of the beneficial response to the signals delivered by transplanted stem cells, encouraging more regenerative activity. That isn't the case for PP1 reduction, which instead acts on the existing cell populations to make them work harder when it comes to driving muscle contraction. Near all of the present efforts to treat heart disease with gene therapy are essentially compensatory in nature. They are trying to improve the present situation in the aging heart without addressing root causes - putting a thumb on regulatory mechanisms that are reacting to the root causes of aging in ways that make things worse. Those causes are still there, however, the cell and tissue damage that accumulates with age. It is quite possible to improve on present day therapies by following this strategy of compensatory change, but radical degrees of improvement, turning back the condition entirely, is outside the bounds of the possible in this paradigm. For that, the causes of age-related decline must be addressed.

Gene Therapy Improved Left Ventricular and Atrial Function in Congestive Heart Failure by up to 25 percent

In heart failure, a weakened or damaged heart no longer pumps blood effectively. This potentially fatal disease is a major cause of morbidity and mortality, especially in elderly patients. Despite this toll, there has been little progress toward any kind of cure. Novel therapeutic approaches, such as gene therapy and cell therapy, hold the promise of complementing or replacing existing therapies for congestive heart failure.

This study featured two independent experiments. The first established the safety of administering a therapeutic gene delivery vector, BNP116, created from an inactivated virus over three months, into 48 pigs without heart failure through the coronary arteries via catheterization using echocardiography. The second experiment examined the efficacy of the treatment in 13 pigs with severe heart failure induced by mitral regurgitation. Six pigs received the gene and 7 received a saline solution.

The researchers determined that the gene therapy was safe and significantly reversed heart failure by 25 percent in the left ventricle and by 20 percent in the left atrium. Heart failure often results in enlarged hearts, and the team found a 10 percent reduction of heart size in the affected animals. Heart failure in the cohort of pigs treated with saline worsened. The research team plans to study the same gene therapy in a human trial starting next year.

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. This study sought to determine the therapeutic efficacy of a re-engineered adeno-associated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy.

Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction and adjusted dP/dt maximum. Moreover, BNP116.I-1c-treated pigs also exhibited a signi´Čücant increase in left atrial ejection fraction at 2 months after gene delivery. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs.


Gene therapy is a great break through this should be funded and more study should be conducted.

Posted by: Jeff Anderson at September 30th, 2017 1:29 AM

Would like to know latest drugs in this field. For damaged left ventricle.

Posted by: Choyi at March 30th, 2019 12:06 PM
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