Gene and Cell Therapy Approaches Hold Promise for Usher Syndrome

Zheng-Yi Chen, DPhil

Zheng-Yi Chen, DPhil, associate scientist, Eaton-Peabody Laboratories, Mass Eye and Ear, and associate professor, Otolaryngology–Head and Neck Surgery, Harvard Medical School, and his colleagues are currently conducting preclinical research that may ultimately contribute to the development of a novel gene editing treatment for Usher syndrome, a rare disease with great unmet need. In honor of Usher Syndrome Awareness Day, which is observed annually on September 21 by the patient and clinician communities, CGTLive® reached out to Chen to learn more.

Chen gave some background information about the disease itself and the current state of care for patients. He also discussed his lab's own research and pointed out other ongoing research projects at other institutions. He concluded with an optimistic message for the community.

CGTLive: Can you give some background on what Usher syndrome is, the current landscape of care, and what unmet needs remain for this patient population?

Zheng-Yi Chen, DPhil: Usher syndrome is a rare genetic disorder characterized by hearing loss and vision impairment. Usher syndrome results from mutations in several genes essential for the development and function of sensory cells in the inner ear and retina.

Currently, there is no cure for Usher syndrome. Management treatments focus on addressing hearing and vision impairments, including cochlear implants for severe to profound hearing loss and hearing aids for mild to moderate hearing loss; low vision aids, vision rehabilitation training, and Braille instruction for those with significant vision loss.

For Usher patients, the quality of life and independence are profoundly impacted by the dual sensory impairment. As such, developing treatments to restore or preserve hearing and vision remains an urgent, unmet medical need.

Can you discuss your research into Usher syndrome and any key findings?

Our work focuses on the development of gene editing to treat hearing loss and vision loss in the Usher syndrome type 2A (Ush2A), the most common form of Usher syndrome. Ush2A patients suffer from congenital hearing loss and progressive vision loss. The Ush2A gene has a large size for which the conventional adeno-associated virus (AAV) vector-based gene therapy method, similar to the one used in our OTOF clinical trial, does not work. Instead, we used a gene-editing strategy called exon skipping, to target the DNA sequence that harbors the most frequent Ush2A mutations. By this approach, we can eliminate the mutation-carrying DNA and restore the production and function of the Ush2A protein missing in patients. We have shown that in the cultured inner ear organ and in a transgenic mouse model, this strategy leads to functional inner ear sensory cells (hair cells). We are working with our collaborator, Drs. Qin Liu and Jason Comander of Mass Eye & Ear and Harvard Medical School, to demonstrate the restoration of hearing and vision in Ush2A mouse models.

Can you speak to the potential for gene therapy or cell therapy approaches in general to address unmet needs in Usher syndrome?

Both gene therapy and cell therapy have great potential to treat Usher syndrome. Gene therapy has been used to successfully restore hearing and vision by targeting different genes and can be applied to Usher syndrome. Cell therapy (e.g. stem cell transplant) may be more effective for the retina than the inner ear due to the easy accessibility.

Are there any other promising treatments for Usher syndrome in development now that you know of and can discuss?

There are many exciting developments in treatments for Usher syndrome, including Ush1B, Ush 1F, and Ush2C in animal models. To move the work to patients, the treatment efficacy has to be demonstrated in animal models by the intervention applicable to humans. For example, the human newborn inner ear is fully mature. As a result, it is important to show our treatment can work in mature animal inner ears before moving the work into a clinical phase.

What is your main message to doctors and the broader healthcare community for Usher Syndrome Awareness Day in 2024?

We are at an unprecedented moment where treatments for Usher syndrome can become realities in the near future. We need the involvement of everyone and to double our efforts to make it happen. There are successful gene therapies for hearing loss and vision loss, from which we can learn a great deal in developing treatments for Usher syndrome. I am excited and hopeful for the promise of new treatments for Usher syndrome.

This transcript has been edited for clarity.