Key Findings and Next Steps

Where do we want our hair cell regeneration research to be in three years’ time, and what will it take to get us there?

By Lisa Goodrich, Ph.D.

The Hearing Restoration Project is at an important juncture, approaching the end of the consortium’s current three-year plan. As we plan for the next cycle and as HHF starts its new fiscal year this fall, we are sharing key findings and next steps.

Here are research highlights from the past year:

• Advanced analyzing large data sets as a group. Data analysis is at the core of what we do daily as researchers, but there is a good deal we have learned about how to coordinate analysis of this enormous amount of data among our three working groups—broadly, 13 primary investigators and their labs—plus me (the scientific director), and the HRP data analyst.

• Produced a list of “pan” (global) hair cell genes that will be a useful tool for the HRP and the field at large. This list is truly a product of terrific synergy among HRP researchers, whose collective knowledge inspired both how we did the analysis and how we think about the results.

• Found success using combined gene expression to stimulate the formation of hair cell-like cells from non-sensory cells in animal models. Demonstrating ways to initiate reprogramming of cells is an important step toward regenerating mature, functional hair cells in the future.

• Updated information on gene delivery systems to confirm that they are robust enough to be used for intermediate screening—the testing of identified candidate genes to see if they can initiate the growth of new hair cells. We are also moving toward delivery systems that can ultimately be used as therapies.

• Continuing to compare the epigenetic mechanisms that influence whether supporting cells express hair cell genes in various species and tissues that do or do not undergo hair cell regeneration. We know from other regeneration research—such as in the retina—that data from a number of species will be key to identifying effective mechanisms to stimulate the development of fully functional cells.

What’s Next?

Having completed the hair cell analysis this year, the Integrative Analysis working group will shift their attention to supporting cells. Supporting cells support existing hair cells, as the name implies, but they also are the cells that divide to form new hair cells. Supporting cells present new challenges, as they are diverse and vary in how they respond to hair cell damage.

This group is coordinating with the Cross-Species Epigenetics working group to expand data collection for the cells we ultimately wish to target, namely adult mammalian supporting cells. A greater understanding of how different types of supporting cells produce hair cells across a variety of contexts is needed for us to be able to identify key nodes for intervention—the relevant molecules and pathways that stimulate regeneration of hair cells.

The HRP is also discussing an increased focus on supporting cells in the Reprogramming and Gene Delivery working group, to identify what is happening in the supporting cells during reprogramming and not just in the hair cell-like cells being created. The group remains focused on improving the number and quality of hair cell-like cells that can be generated.

There is a need for screening platforms that will provide efficient, reproducible, and reliable measurements of outcomes. This will be vital in allowing the HRP (and other groups) to work more efficiently and recognize when we have indeed realized fully functional hair cells. We agreed that we may benefit from soon creating a new, fourth working group dedicated to screening.

Gene Therapy and Collaboration

Consortium members are heartened by the successful use of gene therapy to reverse congenital hearing loss caused by variants of the otoferlin gene. These clinical trials are an encouraging demonstration of the potential for gene therapy, which will be even greater once there is a way to regenerate hair cells. The loss of hair cells occurs not only in many forms of congenital deafness but also in hearing loss caused by multiple genes and by noise and aging. It is this last category that represents the largest number of people living with hearing loss.

The news about these trials also underlines how the hearing field, while relatively small, includes many talented scientists, labs, and teams working on the auditory and vestibular systems from a variety of directions. It is incredibly important to me and members of the HRP that the consortium is able to share its work with and contribute to and collaborate with the wider hearing and balance field.

To this end we remain committed to making findings available through the gEAR (gene Expression Analysis Resource), the preeminent data sharing and visual analysis tool in the ear field that received early and ongoing funding from Hearing Health Foundation.

We are also finalizing the first full-consortium article for publication, which will summarize everything HRP has learned about pan hair cell genes so far, providing a comprehensive resource for the field at large. Plans are also in motion for a second full-consortium paper, this one focusing on supporting cells.

The HRP has a unique role in that we are working on science that would not be funded by the National Institute on Deafness and Other Communication Disorders—the largest funder of hearing research in the world—and that typical labs would not be able to dedicate much time to because the work is deemed too “risky” and requires a breadth of expertise rarely found in a small research group. The HRP, because it brings together 13 investigators and their labs, has not only this deep expertise but also the agility and bandwidth to pursue innovative approaches.

Our HRP scientists are scouring numerous cell types and hundreds of genes across four species to identify potential targets for dedicated trials and investment. This kind of research cannot be completed on a single grant, and much of the basic science we do is not yet ready to be developed further by biotech and pharmaceutical companies. But this is precisely the methodical, interdisciplinary research that needs to be done if we are going to find effective and safe gene and drug therapies to treat hearing loss.

While the path to hair cell regeneration looks long, and it is indeed biologically complicated, we are confident in the steps we have laid out for this coming year and beyond. I look forward to sharing more of our results and outcomes with you in the coming months.

Lisa Goodrich, Ph.D., is the scientific director of the HRP. She is a professor of neurobiology at Harvard Medical School.

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