We are advancing a deep and diverse pipeline of therapeutic programs intended for rare diseases, such as genetic hypertrophic cardiomyopathy (gHCM) and genetic arrhythmogenic right ventricular cardiomyopathy (gARVC), as well as for more prevalent forms of heart disease such as dilated cardiomyopathy (DCM) and heart failure with preserved ejection fraction (HFpEF).
MYBPC3 Gene Therapy Program for Genetic HCM
We are developing an AAV-based gene therapy designed to deliver a functional MYBPC3 gene in adults and children with gHCM due to MYBPC3 gene mutations, estimated to affect more than 115,000 patients in the United States. These mutations can cause the heart walls of affected individuals to become significantly thickened, leading to fibrosis, abnormal heart rhythms, cardiac dysfunction, heart failure (HF), and sudden cardiac death in some adults and children. Based on publicly available information to date, we believe there are currently no approved treatments that address the underlying genetic cause of this disease.
Our product candidate, TN-201, uses a differentiated approach designed to enable robust expression of the MYBPC3 gene in the heart. We have demonstrated significant and durable disease reversal and survival benefit in a relevant murine model after a single dose, as well as tolerability in mice and non-human primates (NHPs).
The program is currently in IND-enabling studies, and we have obtained feedback from multiple regulatory agencies, including the FDA, to guide our path to clinical development. TN-201 has also been granted Orphan Drug Designation (ODD) by the FDA. We intend to submit an IND or CTA to the FDA or EMA, respectively, in 2022.
PKP2 Program for Genetic ARVC
We are developing an AAV-based gene therapy designed to deliver a functional PKP2 gene in adults with gARVC due to PKP2 gene mutation, estimated to affect more than 70,000 patients in the United States. These mutations can cause enlargement of the right ventricle in affected individuals, replacement of heart muscle with fibrotic tissue and fatty deposits, and severely abnormal heart rhythms (arrhythmia) that can make it harder for the heart to function properly and result in sudden cardiac death in some adults and children. Based on publicly available information to date, we believe there are currently no approved treatments that address the underlying genetic cause of this disease.
We have demonstrated prevention of disease progression and survival benefit in a murine model after a single dose. Based on publicly available information to date, we believe these data are the first known demonstrations of durable disease modification, survival benefit, and prevention of arrhythmia using an AAV:PKP2 gene therapy construct.
This program is currently at the candidate selection stage.
DWORF Gene Therapy Program for Dilated Cardiomyopathy (DCM)
We are developing an AAV-based gene therapy designed to deliver the DWORF gene for patients with DCM, estimated to affect about one million patients in the United States. DCM is a progressive and life-threatening disease that causes left ventricle (LV) enlargement, LV wall thinning, insufficient contraction, reduced blood flow, ventricular arrhythmias, and can result in premature morbidity and need for heart transplant in affected individuals. DWORF is a muscle specific micro-peptide first discovered by our co-founder Eric Olson, Ph.D. that acts on the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) pathway, widely considered to be a promising target in HF.
We and our academic collaborators have accumulated significant preclinical in vivo proof-of-concept evidence for the therapeutic benefit of overexpression of the DWORF gene in multiple murine models, including models of gDCM and HFrEF, as well as tolerability in murine models. Based on publicly available information to date, we believe these are the first demonstrations of the potential benefit of AAV:DWORF.
This program is currently at the candidate selection stage.
HDAC6 Inhibitor (HDAC6i) FOR HFPEF AND GENETIC DCM
We are developing a HDAC6i small molecule for various forms of HF, including HFpEF. This disease involves systemic inflammation, left ventricular hypertrophy, fibrosis, and diastolic dysfunction resulting in high morbidity and mortality in affected individuals. HFpEF is one of the greatest areas of unmet need in heart disease with more than three million patients in the United States and currently no approved disease-modifying therapies.
Our product candidate, TYA-11631, is a differentiated compound with unique chemical structures and high specificity for HDAC6. We have demonstrated in vivo activity of our HDAC6i molecules in multiple animal models, including significant disease reversal in two different models of HFpEF as well as tolerability in mice and NHPs. Based on publicly available information to date, we believe TYA-11631 is the first HDAC6i being developed for heart disease.
We have initiated IND-enabling activities and intend to submit an IND to the FDA in 2022.
Reprogramming Program for Heart Failure Due to Prior Myocardial Infarction (MI)
We are developing an AAV-based approach to cellular regeneration that involves converting (or reprogramming) existing cardiac fibroblasts (CFs) within the heart to turn into new cardiomyocytes (CMs) and to replace cells permanently lost due to MI. There are estimated to be more than four million patients in the United States living with HF due to prior MI. The loss of CMs in affected individuals permanently impairs heart contraction, leading to HF and potentially fatal arrhythmias, and the death of approximately 5% to 10% of MI survivors within the first year. There are currently no approved treatments that address the underlying loss of heart tissue.
The potential utility of our unique approach to creating new CMs was first demonstrated by our co-founder Deepak Srivastava, M.D. We have discovered a proprietary combination of three genes that can drive robust in vivo reprogramming of CFs to CMs when delivered together in a single AAV capsid. We have demonstrated significant and durable disease reversal as well as tolerability in multiple small and large animal models. Based on publicly available information to date, we believe our results in a pig model of HF due to prior MI represent the first-ever successful demonstration of the potential beneficial effect of this approach in a human-sized heart.
This program is currently at candidate selection stage.