Acceleration of heart failure in the SHHF rat model

DESCRIPTION (provided by applicant): Myogen's goal is to discover novel disease-modifying therapies for heart failure (HF). Approximately 700,000 individuals are affected each year by HF, which is a common endpoint of many cardiovascular diseases. The annual health care costs for HF patients in the United States is estimated at $10-40 billion. Clearly, novel treatment approaches are necessary. Animal models serve a dual purpose in drug discovery. Putative drug targets need to be validated, and lead compounds identified by high throughput screens need to be evaluated. To this end, Myogen proposes to establish and test the SHHF (Spontaneously Hypertensive and Heart Failure) rat as a versatile animal model for target validation and drug testing in vivo. Since the SHHF rat responds favorably to treatment regimens used in human HF therapy, this model should be adaptable to Myogen's drug discovery efforts. It is proposed to accelerate the development of cardiac hypertrophy and HF in the SHHF model by surgical and/or dietary methods. The investigators hypothesize that the genetic predisposition of the SHHF rat will lead to a faster and more pronounced response, permitting a more rapid evaluation of targets and lead compounds in vivo. In the present Phase I application, Myogen will characterize physiologic and molecular parameters related to the natural and to the forced progression of cardiac hypertrophy and HF in the SHHF rat. This work will establish the usefulness and versatility of this animal model. In Phase II, Myogen will demonstrate that the SHHF model, in combination with the methods to accelerate cardiac hypertrophy and HF identified in Phase I, is useful and appropriate for the validation of drug targets and for the evaluation of lead compounds in vivo. Phase III will focus on the commercialization of the novel accelerated HF model, and its use for in vivo support of lead optimization and advancement of drug candidates to clinical testing.