ARV Cardiomyopathy Gene Therapy Gets Orphan Drug Designation


In preclinical research, TN-401 was shown to significantly increase the lifespan of PKP2-knock-out mice.

Tenaya Therapeutics’ TN-401, an investigational adeno-associated virus (AAV)-based gene therapy intended to treat arrhythmogenic right ventricular cardiomyopathy (ARVC), has been granted orphan drug designation by the FDA.1

TN-401 is intended to deliver a functional copy of plakophilin-2 (PKP2), the disease-targeted gene in approximately 40% of patients with ARVC, via an AAV9 vector in a single dose. Preclinical data presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16–19, 2022, in Washington, D.C., demonstrated promising efficacy and safety for the therapy in a cardiac specific PKP2 knock-out mouse model (Pkp2-cKO).2 

TN-401 was shown to significantly increase the lifespan of the mice. Furthermore, it demonstrated the capability to decrease ventricular arrhythmias, prevent fibrosis, and restore desmosomes and gap junctions in a model of disease onset. In a model of disease progression, TN-401 demonstrated the ability to reverse right ventricular (RV) enlargement and to prevent decline of left ventricular function. 

“A single dose of cardiac AAV:PKP2 gene delivery significantly improves life span of Pkp2-cKO ARVC mice by restoring expression of desmosome components; preventing and reversing adverse right ventricular remodeling; maintaining and improving ventricular functions; preventing cardiac fibrosis, and reducing ventricular arrhythmia event frequency and severity,” lead author Jane Yang, PhD, senior scientist, Tenaya Therapeutics, and colleagues wrote in the poster.2 “Additional studies on AAV:PKP2 gene therapy efficacy show a dose-dependency in disease modification and survival benefit. Safety evaluation of AAV:PKP2 in wild-type mice shows no adverse effects on cardiac function and no changes in tissues examined. Our preclinical results demonstrate that cardiac AAV:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.”

The authors noted that additional research is needed to support these findings. At the time of the conference, it was noted that TN-401 was currently entering into investigational new drug (IND)-enabling studies.

Before the end of 2022, Teneya Therapeutics also plans to begin a natural history study that will recruit participants that carry ARVC PKP2 gene mutations to gather information about treatment history and seroprevalence to AAV antibodies. The company expects to submit an IND application to the FDA for TN-401 in 2023.

“ARVC has an estimated prevalence in the general population of 1:2000 with the mean age of presentation before 40 years of age,” Yang and colleagues added in the poster.2 “Progressive disease eventually leads to moderate to severe RV dysfunction in approximately 45% of patients. Clinical management of ARVC patients includes lifestyle modification, pharmacological treatment, catheter ablation, ICDs, and heart transplantation. Based on publicly available information to date, we believe there are no approved treatments that address the underlying genetic causes of this disease. Therefore, a new treatment paradigm is needed to prevent disease onset and disease progression.”

1. Tenaya Therapeutics receives orphan drug designation from the U.S. Food and Drug Administration for its gene therapy for genetic arrhythmogenic right ventricular cardiomyopathy. News release. Tenaya Therapeutics. November 28, 2022. 
2. Wu I, Greer-Short A, Zeng A, et al. Cardiac AAV:PKP2 gene therapy reduces ventricular arrhythmias, reverses adverse right ventricular remodeling, improves heart function, and extends survival in a PKP2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy. Presented at: American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16–19, 2022, Washington, D.C. and virtual.Abstract #630
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