Dr. Zheng-Yi Chen Named Co-PI of $4 million NIH Grant for Gene-Editing Solutions to Usher Syndrome

August 30, 2022

Zheng-Yi Chen, DPhil, Associate Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Associate Scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear, has been named a Principal Investigator (PI) of a $4 million, multi-PI R01 grant from the National Institutes of Health (NIH), which will fund the development of gene-editing treatments for different forms of Usher syndrome, a rare hereditary condition responsible for nearly half of all deaf-blindness cases.

The R01 NIH grant will span multiple institutions over five years and was formally awarded to Xue Zhong Liu, MD, PhD, FACS, Professor and Vice Chairman of Otolaryngology at the University of Miami School of Medicine, who will serve as its main PI. Karl Koehler, PhD, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Research Associate at Boston Children’s Hospital, will serve as a collaborator under the grant.

Usher syndrome is manifested by hearing loss and blindness due to mutations in the genome resulting in defective Usher proteins. Without healthy versions of these proteins, sensory cells in the eyes and ears are rendered ineffective, preventing a person from seeing or hearing. While adeno-associated vectors (AAVs) can correct mutations by carrying healthy versions of a gene to an affected cell, the technique becomes ineffective if the healthy gene is too big to fit inside the vector. The massive size of the genes responsible for producing healthy Usher proteins far exceeds the traditional capacity of an AAV, and scientists have long sought an alternative gene-editing technique.

With support from their grant, Drs. Liu, Chen and Koehler will test the ability of several gene-editing techniques to fix mutations in genes responsible for multiple types of Usher syndrome. Dr. Chen has already patented one of the techniques, referred to as exon skipping, whcih relies on CRISPR/Cas9 editing tools to bypass small chunks of a gene, known as exons. By bypassing, or “skipping,” over mutated chunks of the gene, the technique could produce a slightly shortened, albeit effective, gene capable of producing healthy Usher proteins, thereby restoring function to sensory cells in the eyes and ears. 

Through their study, the researchers will likely identify the most effective treatment paradigm for each type of Usher syndrome by testing each gene-editing technique in both animal models and human inner-ear organoids.

“Exon-skipping offers a glimpse into what new gene therapies based on gene editing might have in store for the future of medicine,” Dr. Chen said. “We’re excited by the seemingly endless possibilities it could open for similar hereditary conditions caused by mutations to much larger genes. Given many successful clinical trials by gene editing treatments, it is our goal to bring our work to the clinic as quickly as possible.”