Gene Based Therapy for Congestive Heart Failure

DESCRIPTION (provided by applicant): Congestive heart failure is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential in diseases such as congestive heart failure. Improvement in our understanding of the molecular mechanisms of heart failure, along with the development of novel and safer vectors for gene delivery, have led to the identification of novel targets that are difficult to manipulate pharmacologically but may bemore amenable to gene therapy. In the last few years calcium cycling abnormalities and specifically deficiencies in sarcoplasmic reticulum calcium uptake have been hallmarks of advanced heart failure. The complex of SERCA2a-phospholamban-Protein phospatase 1 has been difficult to target pharmacologically. However the encouraging results from the CUPID trial in which AAV1.SERCA2a gene transfer was found to be safe and demonstrated benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure in a phase 2 study, has once again validated calcium cycling as being an important target for heart failure treatment. For this reason, I-1c with its additional benefits is emerging s an important and valid target for the treatment of heart failure. Even though AAV vectors have been shown to be safe in a number of trials including the CUPID trial, they have the following limitations when used in the setting of heart failure: 1) they are not specific for the heart and 2 pre-existence neutralizing antibodies to any individual serotype would result in the exclusion of a large percentage of the patients. In fact in the CUPID trial 50% of the screened heart failure patients had to be excluded because they had neutralizing antibody titers against AAV1. Nanocor Inc. has developed a chimeric of AAV that more specifically targets the heart and escapes the inherent immunity in patients. We have proposed to use of these novel chimeric vectors, which are also known as Bio Nano Particles (BNP), to directlytarget I-1 in experimental models of heart failure. In this phase 1 application, we will carry out a dose-escalation efficacy study of BNP116.CMV.I1c by Intra-Coronary Infusion in a pre-clinical model of heart failure. PUBLIC HEALTH RELEVANCE: While progress in conventional treatments for heart failure is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. It is now apparent that gene therapy is a viable option forthe treatment of congestive heart failure. To this end, Nanocor has developed a cardiotropic chimeric of AAV vector targeting the inhibitor 1 protein in cardiomyocytes which it will test in ths phase 1 SBIR grant.