SBIR-STTR Award

The goal of this proposal is to develop a novel therapy for molecular inotropy, specifically, viral-mediated myocardial delivery of the calcium regulatory protein SERCA 2a (sarcoplasmic reticulum Ca 2vATPase) to large animals exhibiting heart failure in an attempt to restore function and improve survival without worsening energetic parameters. Congestive heart failure (CHF) represents an enormous clinical problem demanding effective therapeutic approaches. Despite advances in traditional approaches to its treatment, including pharmacologic management, myocardial revascularization, mechanical assist devices, and transplantation, CHF remains a leading cause of death worldwide. Therefore, a novel therapy aimed at decreasing the morbidity and mortality of CHF and improving the quality of life for millions of patients is particularly attractive. Cardiac gene therapy has shown promise in early animal studies and lends itself to the treatment of heart failure. A defect in intracellular calcium handling is known to be a key abnormality in both human and experimental CHF. Deficient Ca 2vuptake by the sarcoplasmic reticulum (SR) during relaxation in failing hearts from humans and animal models has been associated with a decrease in the expression and activity of SR Ca2+ATPase (SERCA2a). Our preliminary work over the last five years have shown that 1) Gene transfer is an effective means of introducing the SERCA2a gene into myocytes in vitro and in vivo and 2) that increasing the expression of SERCA2a restores contractility and normalizes intracellular calcium cycling in a rodent model of CHF. We are now extending our experiments from rodents to porcine models. We aim to 1) determine the efficiency of transduction of viral vectors in cardiomyocytes isolated from pig hearts; 2) determine the efficiency of transduction of the AAV vectors and El-E4 deleted recombinant adenovirus following gene transfer in vivo in pigs; 3) test the proximal human brain natriuretic (hBNP) promoter (-408 to +100 relative to transcription start site) for the ability to be induced by pressure-overload versus ischemia.

Thesaurus Terms:
biotechnology, calcium transporting ATPase, gene therapy, heart failure, therapy design /development, transfection /expression vector bioenergetics, calcium flux, cardiac myocyte, disease /disorder model, gene delivery system, gene expression, genetic promoter element, genetic transduction, nerve /myelin protein, sarcoplasmic reticulum adeno associated virus group, recombinant virus, swine

Heart failure (HF) represents an enormous clinical problem demanding effective therapeutic approaches. Despite advances in traditional approaches to its treatment, including pharmacological management, myocardial revascularization, mechanical assist devices, and transplantation, heart failure remains a leading cause of death worldwide. Therefore, a novel therapy aimed at decreasing the morbidity and mortality of heart failure and at improving the quality of life for millions of patients is particularly attractive. Deficient calcium uptake by the sarcoplasmic reticulum during relaxation in failing hearts from humans has been associated with a decrease in the expression and activity of SR Ca2+ATPase (SERCA2a) and contractility of the heart. We have previously demonstrated that: 1) adenoviral gene transfer is an effective means of introducing the SERCA2a gene into myocytes in vitro and in vivo in rodents and now in pigs, 2) that increasing the expression of SERCA2a restores contractility and normalizes intracellular calcium cycling in a rodent model of pressure-overload hypertrophy and 3) that adenoviral gene transfer to cardiac myocytes isolated from failing human hearts results in restoration of contraction and relaxation properties. In order to develop SERCA2a as a therapeutic target the following remains to be accomplished: 1) the proper vector and promoter must be selected, and 2) efficacy, safety, and toxicity studies must be performed in two species. We have addressed in part the selection of the proper vector, developed a delivery method as well as demonstrated early proof of concept studies showing efficacy during our Phase 1 application. Two species (one rodent and one non-rodent) must be studied for FDA approval. It is hoped that by examining this novel therapy for molecular inotropy, the company will be able to validate SERCA2a as a therapeutic target. Here, we propose to perform needed studies that will position us for any additional studies requested by the FDA which would be required to file a successful Investigational New Drug application at the end of Phase 3 funding