Engineered polymeric adjuvants for heart-redirected targeting and gene therapy

In this project, we aim to develop and improve the delivery of various therapies, including adeno-associated viral (AAV) and nanoparticle (NP) gene therapy to the heart. The impetus for this project is a high unmet need for cardiomyopathies that do not have current treatments. Cardiomyopathy is an umbrella term for disorders of cardiac muscles. Collectively, these disorders are highly prevalent, and many lack specific treatment options. Because most gene therapies are one-time, single-dose treatments, improving heart targeting becomes critical to achieve adequate efficacy. Systemic delivery of AAV or NP vectors in adult, often overweight, patients is fraught with challenges related to the low transduction of cardiomyocytes and the life-threatening immune response. By enhancing the delivery of genetic information to the heart and reducing its sequestration by the liver, we would be able to increase efficacy and improve safety of these therapeutics. Based on the discoveries in our lab, we hypothesized that by co-delivering AAV, NPs, oligonucleotides, antibodies or other therapeutics with an engineered polymeric adjuvant, a synthetic enhancer, will improve the therapeutic index of these therapeutics. We also hypothesized that this technology that we call heart-redirected targeting (HRT) has a potential to enhance the delivery of any therapeutic entity. This hypothesis is supported by the preliminary studies on mechanism of action of HRT and examples of delivery of various therapeutic modalities. Therefore, in this proposal, we aim to: 1) test the risk/benefit of HRT; 2) investigate the generality and reproducibility of the HRT; 3) elucidate the mechanism of action of HRT in human-relevant cellular models; 4) test the long-term efficacy of HRT with AAV carrying frataxin (FXN) transgene in genetic mouse model of Friedreich’s ataxia (FA). In order to decrease mortality in FA, it is critical to treat cardiomyopathy, which is the dominant cause of death among FA patients. If successful, this work will have an unprecedented impact on drug delivery and gene therapy, because the HRT system is agnostic to the delivery vehicle, opening a possibility of cardiac targeting with a wealth of approaches developed to date.