Highlights From the Hearing Restoration Project

By Lisa Goodrich, Ph.D.

Transcription factors Gfi1, Atoh1, Pou4f3, but not Atoh1 or Gfi1+Atoh1, can reprogram 8-day-old greater epithelial ridge (GER) cells into hair cell-like cells. Arrows point to the GER region in the Rosa26-GAP cochlea, where many reprogrammed hair cells are observed. Credit: Iyer et al./eLife

Hearing Health Foundation’s Hearing Restoration Project (HRP) continues to make significant advances in scientific research toward understanding how some animals are able to restore their own damaged inner ear hair cells. Our aim is to uncover and apply this knowledge to humans, bringing us closer to a cure. The projects of the HRP’s three working groups continue to make progress, with data collection and analysis continuing in line with the aims and milestones in this year’s project timelines.

Here are highlights of recent accomplishments from the past year, details of which are forthcoming in a number of publications, some currently under review and others in preparation.

Major Funding Resulting from HRP Work

• Andy Groves, Ph.D.: National Institutes of Health/National Institute on Deafness and Other Communications (NIH/NIDCD) award, “Enhancing Atoh1 function in hair cell regeneration,” 2022–2027

• Stefan Heller, Ph.D.: NIH/NIDCD award, “Regenerative pathways in the avian cochlea,” 2022–2027

• Yehoash Raphael, Ph.D.: NIH/NIDCD award, “Enhancing Atoh1 Function in Hair Cell Regeneration,” 2022–2027

Cross-Species Epigenetics Working Group

• Refined a sorting process to generate large pools of pure supporting cells and hair cells from the zebrafish, and began defining the molecular details of how zebrafish supporting cells produce new hair cells when there is damage

• Gained insights into the mechanisms that shut down hair cell gene expression in supporting cells in the developing mouse 

• Developed a method for performing multi-omic analysis of adult mammalian supporting cells, our target cell population for hair cell regeneration

• Produced multi-omic datasets from the human utricle (a balance organ in the inner ear), an important step toward learning why regeneration fails in humans

• Added Litao Tao, Ph.D., of Creighton University to the group, enhancing our expertise in epigenetic mechanisms

Integrative Analysis Working Group

• Added a dedicated analyst to facilitate and encourage interactions within the consortium

• Completed a cross-species analysis of how roughly 28,000 different genes are expressed in 28 types of hair cells from four species

• Produced a user-friendly app that enables real-time comparison of gene expression among 28 hair cell types and linked it to the gEAR for easy access by anyone in the field

• First public presentation of our collaborative efforts at the most recent Association for Research in Otolaryngology MidWinter Meeting in February 2023

• Generated transcriptomic data for mouse cochlear organoids that will serve as an effective platform for identifying drug candidates in the future

• Improved the gEAR, which enables data analysis and visualization for the entire research community: 

• Added 168 new datasets in 2022 and created a secure section for HRP members to share their data directly

• Created lists of marker genes for easier mining of single-cell RNA-sequencing datasets 

• Created a machine-learning tool that applies patterns from one dataset to another, making it easier to move between cell types and species

Reprogramming and Gene Delivery Working Group

• Demonstrated that a cocktail of three factors can promote the conversion of nonsensory cells into hair cells in the mouse model (see image above)

• Discovered that reprogramming of supporting cells is much more efficient when hair cells are entirely destroyed, illuminating new understanding of the relationship between the two cell types

• Secured encouraging preliminary data on two methods of viral delivery of reprogramming factors to a severely damaged cochlear epithelium, moving us closer to a means of delivering future therapies to the inner ear

Thank you for your ongoing support of Hearing Health Foundation.

HRP scientific director Lisa Goodrich, Ph.D., is a professor of neurobiology at Harvard Medical School. For more, see hhf.org/hrp.

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