IND-enabling study of AAV-mediated TMPRSS3 gene therapy to treat human autosomal recessive hearing loss DFNB8

The National Institute on Deafness and Other Communication Disorders awarded Massachusetts Eye and Ear Infirmary $1.15 million on August 15, 2026, under the Research Related to Deafness and Communication Disorders program (CFDA 93.173) to conduct an IND-enabling study of AAV-mediated TMPRSS3 gene therapy for autosomal recessive hearing loss DFNB8.

The recipient will develop and validate preclinical evidence supporting an investigational new drug application for TMPRSS3 gene therapy in a mouse model of DFNB8, a postlingual progressive hearing loss caused by TMPRSS3 mutations. The work builds on the recipient's successful OTOF gene therapy clinical trial for DFNB9, which restored hearing and speech capability in children with congenital deafness. The current study will characterize a newly developed DFNB8 mouse model (TMPRSS3A306T/A306T) that reproduces the human phenotype and test AAV gene therapy efficacy and safety in that model to support regulatory pathways for human clinical translation.

Performance occurs in Boston, Massachusetts, from August 15, 2026, through June 30, 2031. The assistance type is a Project Grant.

Abstract

And relevance genetic hearing loss affects one in 500 newborns and contributes significantly to general populations with hearing loss. Over 150 deafness genes are known, and more are to be identified. There are no approved treatments for genetic hearing loss except for cochlear implants. AAV-mediated gene therapy has shown to be safe and efficacious in animal models of human genetic hearing loss. We have recently conducted the first successful unilateral and bilateral otof gene therapy trial for genetic hearing loss DFNB9 in children born with complete deafness. Gene therapy restored hearing, speech capability, the ability to localize sound sources, and improved speech recognition in noisy environments. This is the first time in history that hearing loss has been reversed with hearing restoration since the invention of cochlear implants over 60 years ago. These results usher in a new ERA of novel gene therapy to treat human genetic hearing loss. The otof clinical trial demonstrates the feasibility and translatability of gene therapy for genetic hearing loss from animal (mouse) models to human patients. IT establishes a path by which the development of gene therapy for other genetic hearing loss for humans can be accelerated. Based on the successful otof clinical trial, we propose to conduct an IND-enabling study of AAV gene therapy of TMPRSS3 for human recessive genetic hearing loss DFNB8. DFNB8 is a postlingual progressive hearing loss due to mutations in TMPRSS3, for which cochlear implant is the only treatment option. TMPRSS3 encodes a type II membrane serine protease, is expressed in developing hair cells and spiral ganglions, and is required for their survival. We have created and characterized a DFNB8 mouse model TMPRSS3A306T/A306T with delayed onset and progressive hearing loss that reproduces the human DFNB8 phenotype. We have demonstrated that by AAV gene therapy in aged (13 months of age) TMPRSS3A306T/A306T mice, human TMPRSS3 robustly rescued hearing to the level of WT mice long term, with the rescue of hair cells and spiral ganglion neurons affected by TMPRSS3 mutations. We have conducted an international multi-center DNFB8/10 patient retrospective natural history study with over 100 patients from six countries and multi-ethnic groups and established genotype-phenotype correlations, disease progression rate, and age distribution. In this proposal, we will leverage the complementary expertise of four core groups to evaluate the hearing rescue efficacy in TMPRSS3A306T/A306T mice and biodistribution and toxicity in wildtype (WT) CBA/CAJ mice with escalating doses of AAV2-HTMPRSS3. We will study the biodistribution and vector tolerability by escalating doses of GLP-grade AAV2-HTMPRSS3 in rhesus monkeys and conduct a prospective natural history study of DFNB8 patients to identify candidates for a clinical trial. We will engage with the FDA with the objective of obtaining feedback on the design of definitive (IND-enabling) preclinical studies, the design of the clinical study, and manufacturing/quality controls needed to initiate human studies. Completing the project will enable US to conduct a first-in-human clinical trial of TMPRSS3 gene therapy in adult DFNB8 patients and provide a road map of gene therapy for progressive hearing loss. Our study aligns with the nidcd strategic plan 2023-2027 theme 3 goal 2 "develop genetic and cellular therapies".