In studying the mechanism of action of Neucardin™, Zensun scientists found that generating an increase in human cardiac specific myosin light chain kinase (cMLCK) might be an effective treatment for heart failure. In order to pursue a gene therapy approach, Zensun independently constructed cMLCK-bearing adeno-associated virus (rAAV9.cMLCK)-the gene expression system for cMLCK. rAAV9.cMLCK specifically infects cardiomyocytes and increases the protein expression of cMLCK, which enhancesthe phosphorylation of myosin light chain (MLC2v) and myocardial sensitivity to Ca2+. This improved myocardial-Ca2+ -sensitivity promotes the contraction of myocardial sarcomeres, thereby enhances cardiac power. Therefore, in summary, rAAV9.cMLCK is a potential gene therapeutic agent for treatment of severe heart failure (NYHA IV grade). (see figure 1).

    Adeno-Associated Virus (AAV) is an ideal gene expression vector with low immunogenicity, high safety, high infection efficiency and strong organ specificity, and has been approved by FDA for clinical trials. Considering its specificity for the myocardium and the efficiency of infection, we chose the AAV9 virus as a carrier to package the target gene cMLCK for cardiomyocyte therapy. The project is currently in the preclinical research stage. The results of animal experiments show that increasing the expression of the cMLCK gene in the heart of rats undergoing heart failure can effectively increase the maximum rate of left ventricular pressure rise (+ dp/dt), increase left ventricular short axis fractional shortening (FS) and reduce mortality. Zensun has received four patents related to this project in China and Europe, and has five additional applications filed. The successful development of rAAV9.cMLCK gene therapy is expected to fill gaps in the treatment of severe heart failure, providing a needed tool to allow patients with severe heart failure to improve their quality of life and prolong their survival.

About Severe Heart Failure

    Severe heart failure (NYHA class IV), is the most serious type, accounting for 5-10% of the total number of heart failure patients, with an annual mortality rate of up to 50% of those affected, making it more lethal than some malignant tumors [1]. Severe heart failure patients cannot engage in any physical activity, and show symptoms of heart failure even in the resting state so that their quality of life is extremely low. Although the standard treatment for chronic heart failure can currently improve cardiac function and slow the heart failure process, the patient's pathological process still continues to deteriorate cardiac function and eventually leads to death. Patients often require special treatment intervention measures and patient mortality remains high [1]. Because of the severe decline in the expression level of ErbB receptors on the surface of cardiomyocytes in patients with severe heart failure, binding of neuregulin is reduced, and thus the treatment effect of Neucardin™ in these patients is also reduced. It is therefore necessary to develop more effective treatments for severe heart failure. In studying the mechanism of action of Neucardin™, Zensun scientists found that cardiac-specific myosin light chain kinase (cMLCK) in downstream signaling pathways is a cardiac-specific protein that phosphorylates ventricular-specific myosin. Light chain 2 (MLC2v), thus promoting sarcomere assembly and intercalated disk connection. cMLCK plays an important role in maintaining the normal function of the heart [2]. Earlier studies found that in the hearts of patients with chronic heart failure, cMLCK gene expression was affected and mRNA and protein levels of cMLCK were significantly reduced. In light of this, Zensun pioneered a gene therapy approach that would directly increase the expression of cMLCK in the cardiomyocytes, Increased expression will effectively activate the downstream signaling pathway, promote sarcomere rearrangement and myocardial relaxation, and play an important role in the treatment of severe heart failure.

[1][1]Friedrich E B, Böhm M. Management of end stage heart failure[J]. Heart, 2007, 93(5): 626-631.
[2]Gu X, Liu X, Xu D, et al. Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin[J]. Cardiovascular research, 2010, 88(2): 334-343.

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