A collaborative research team is pioneering the use of adeno-associated virus (AAV)-mediated gene editing to treat human autosomal dominant hearing loss, with the support of a $16 million grant from the National Institutes of Health (NIH). This initiative focuses on investigational new drug (IND)-enabling studies to facilitate platform clinical trials of genome editing across multiple diseases, potentially revolutionizing treatment approaches for genetic hearing impairments.
The research builds upon earlier findings by Miller School investigators, which identified mutations in the genes responsible for human autosomal dominant deafness-41 (DFNA41) and deafness nonsyndromic autosomal dominant 2 (DFNA2) hearing loss in both human and animal models. Specifically, the team is targeting DFNA41, caused by a mutation in the P2RX2 gene, and DFNA2, resulting from a mutation in the KCNQ4 gene.
Streamlining Regulatory Pathways for Editing Therapy
The study aims to establish a streamlined regulatory process approved by the FDA, utilizing a single delivery vehicle, editor, and delivery route, with two guide RNAs (gRNAs) to target both types of hearing loss. According to Dr. Xue Zhong Liu, the Leonard M. Miller Professor and vice chairman of research in the Department of Otolaryngology-Head and Neck Surgery at the University of Miami Miller School of Medicine, this approach could "open the door to speeding up the development of clinical editing therapy for adult progressive hearing loss."
Understanding DFNA41 and DFNA2
DFNA41 typically manifests as hearing loss beginning at high frequencies between the ages of 15 and 25, gradually affecting other frequencies and progressing from mild or moderate to severe or profound. Patients with DFNA41 are also particularly vulnerable to noise-induced hearing loss. In contrast, DFNA2 presents earlier in life, with hearing loss starting within the first two years, also at high frequencies, and worsening across other frequencies. Treatment for both conditions currently involves hearing aids or cochlear implants, depending on the severity of the hearing loss.
Collaborative Effort and Future Directions
The research is a collaborative effort involving scientists from multiple institutions, including Harvard Medical School, Mass General Brigham, and the Diagnosis and Treatment Center of Genetic Hearing Loss in Shanghai. "The ultimate goal is to be able to develop treatments for as many patients as possible," said Dr. Liu. "Longer term, we believe similar approaches can be used to restore hearing loss caused by aging or other noise damage."
Fred Telischi M.D., M.E.E., FACS, the James R. Chandler Chairman of the Department of Otolaryngology-Head and Neck Surgery at the Miller School, emphasized the transformative potential of this work, stating that it represents "pioneering preclinical discovery research at the UHealth Ear Institute leading to this IND-enabling study aimed at reversing common forms of human, genetic hearing loss."
