Associate Professor of Otolaryngology, Harvard Medical School
PhD Oxford University
Dr. Zheng-Yi Chen’s research interests include the understanding of the causes of hearing loss, the development of treatment by inner ear regeneration, gene editing, and gene therapy.
One of the most common causes of hearing loss is the loss of hair cells, the inner ear sensory cells that detect sound and sense balance. Regeneration of these hair cells in the adult mammalian inner ear has been the most prominent obstacle to overcome. Dr. Chen’s laboratory takes a functional genomics approach to systematically study gene expression patterns during mouse inner ear development.
Dr. Chen's laboratory has identified the retinoblastoma gene (Rb1) as the key gene controlling cell exit in hair cells and supporting cells, with implication in hair cell regeneration in young mammalian inner ears. Using chicken and zebrafish models, they identified key genes including c-Myc in hair cell regeneration in lower vertebrates. They demonstrated that the reprogramming by two factors c-Myc and Notch1 is sufficient to induce proliferation of hair cells and supporting cells in adult and aged mammalian inner ears, resulting in regeneration of functional hair cells.
His laboratory is currently working on elucidating the mechanisms underlying proliferation and regeneration. They are also developing strategies to regenerate adult hair cells for hearing restoration in animal models. Their goal is to develop a treatment for hearing loss by inner ear regeneration in humans.
Dr. Chen’s laboratory also has a long-standing interest in genetic hearing loss. The laboratory has been involved in cloning and characterizing numerous deafness genes. Though more than one hundred genetic deafness genes have been identified, no therapy is currently available. The next frontier in genetic hearing loss is the development of treatment.
The laboratory is applying the transformative CRISPR/Cas9-mediated genome editing technology to treat genetic hearing loss. They developed the delivery of RNP (ribonucleoprotein) into the mammalian inner ear in vivo. They demonstrated RNP delivery of CRISPR/Cas9 genome editing agents into mouse models of human genetic hearing loss with the rescue of hearing. They have produced a pig model for human genetic hearing loss to further advance the work into the clinic. Their work opened a new avenue in developing a treatment for genetic hearing loss by editing based therapy.
Age-related and noise-induced hearing loss (ARHL and NIHL) are considered different entities that require separate treatments. Dr. Chen’s laboratory uncovered that hair cell overexpression of ISL1, an inner ear progenitor gene, resulted in protection from both ARHL and NIHL in mice. Hair cells expressing ISL1 are resistant to damage or cell death (apoptosis). This study underscores a common mechanism underlying ARHL and NIHL.
The laboratory is additionally developing an AAV (adeno-associated virus) based gene therapy for ARHL and NIHL. Dr. Chen’s long-term research goals are to identify genes and functional pathways that govern the development, function and disease state of the inner ear, and to develop multiple approaches as treatment for different types of hearing loss in humans.