Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. As the most common form of heart disease, HF carries substantial morbidity and mortality and has become a major public health issue with a prevalence of over 23 million worldwide. Every year in the USA, more than 550,000 individuals are diagnosed with HF for the first time. Despite the favorable trends in survival during recent decades, HF remains highly fatal; more than 50 percent of patients were dead within five years.

Chronic heart failure (CHF) is a chronic disease where the heart has lost the ability to pump enough blood to the body's tissues. Current pharmacotherapy for heart failure includes the use of diuretics, angiotensin-converting enzyme inhibitors (ACEI), beta blockers, and angiotensin II receptor blockers (ARB). These drugs act through different mechanisms, such as improving sodium excretion, relaxing blood vessels, and slowing heartbeat, and these actions prolong survival and relieve symptoms. However, the efficacy of current pharmacologic therapies is not optimal. None of these drugs can improve the structure and function of cardiomyocytes directly; CHF still represents a growing clinical challenge in need of novel therapeutic approaches. Whether it is possible to treat CHF by repairing injured cardiomyocytes remains a worthwhile goal.

The ErbB family of protein-tyrosine kinases has been linked to the regulation of diverse cellular events such as proliferation, senescence, differentiation, and apoptosis. ErbB receptors and their specific ligand, neuregulin-1 (NRG-1), play a critical role in cardiac development. After years of innovative drug development focusing on ErbB receptor tyrosine kinases and their downstream signaling pathways, Zensun has uncovered the unique relationship between the NRG-1/ErbB pathway and heart disease.

Zensun has uncovered the critical role NRG-1 and its receptor ErbB2/ErbB4 plays in the adult heart, including the promotion of cell growth and survival, the maintenance of sarcomeric structural organization, and the enhancement of systolic/diastolic function. Based on this discovery, Zensun has developed a novel drug, recombinant human neuregulin-1 (rhNRG-1, Neucardin®). Phase I/II trials have been completed in both the USA and China, and a large Phase III trial is ongoing in China. Another crucial advance in Zensun’s studies was made when a downstream gene in the ErbB2/ErbB4 pathway, cardiac-specific myosin light kinase (cMLCK), which targets the myosin regulatory light chain (MLC2v), was identified as an important regulator for sarcomere assembly and heart contractility. Zensun has begun development of a novel gene therapy approach to treat heart failure – using recombinant AAV serotype 9 to deliver the cMLCK gene (rAAV9.cMLCK). The cardiomyocyte therapies developed by Zensun are based on long-term research and an in-depth understanding of cardiac cell biology. These insights have revealed promising new treatment options for heart failure.

Neucardin® 和rAAV9.cMLCK心肌细胞治疗作用靶点示意图


[1]WRITING C M, Yancy C W, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[J]. Circulation, 2013, 128(16): e240.

[2]Bui A L, Horwich T B, Fonarow G C. Epidemiology and risk profile of heart failure[J]. Nature Reviews Cardiology, 2011, 8(1): 30-41.

[3]Levy D, Kenchaiah S, Larson M G, et al. Long-term trends in the incidence of and survival with heart failure[J]. New England Journal of Medicine, 2002, 347(18): 1397-1402.

[4] Liu X, Gu X, Li Z, et al. Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy[J]. Journal of the American College of Cardiology, 2006, 48(7): 1438-1447.

[5] Luo C, Xu L, Zheng S, et al. Computational analysis of molecular basis of 1: 1 interactions of NRG‐1β wild‐type and variants with ErbB3 and ErbB4[J]. Proteins: Structure, Function, and Bioinformatics, 2005, 59(4): 742-756.

[6] Xu Y, Li X, Zhou M. Neuregulin-1/ErbB signaling: a druggable target for treating heart failure[J]. Current opinion in pharmacology, 2009, 9(2): 214-219.

[7]Li Z, Mei Y, Liu X, et al. Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners[J]. Cellular signalling, 2007, 19(3): 466-471.