About

David P. Corey is the Bertarelli Professor of Translational Medical Science and a Professor of Neurobiology at Harvard Medical School. His research focuses on the assembly of proteins in the mechanotransduction complex, gene therapy for dominant disorders, ion permeation and gating of the hair-cell transduction channel, and the development of novel gene therapies to treat Usher Syndrome Type 1F, including gene editing, dual-AAV delivery, and mini-PCDH15 approaches. His work aims to advance understanding and treatment of sensory disorders, particularly those related to hearing and balance. He is actively involved in translational research efforts to develop innovative therapeutic strategies for inner ear conditions.

Research topics

• Neuroscience
• Genetics
• Biology
• Cell biology
• Biophysics
• Molecular biology
• Medicine
• Virology
• Anatomy

Selected publications

• Evolutionary tuning of an auditory transduction channel

  Current Biology · 2026-03-25

  articleOpen accessSenior author

  TMC1 and TMC2 are mechanosensory ion channels of the vertebrate inner ear that mediate hearing and balance. How these channels open in response to mechanical force remains unresolved. Through comparative analyses of TMCs across eukaryote species, we find that TMC1 and TMC2 arose in vertebrates by gene duplication and evolved elaborate extracellular loops. Structural models demonstrate that the loop between transmembrane domains 1 and 2 arches over the channel pore and lies near TMIE, an auxiliary protein essential for function. In mammals, this loop shows signatures of positive selection and contains multiple sites linked to hereditary deafness, consistent with TMC1's specialization for auditory function. Electrophysiological recordings from mouse Tmc1/Tmc2-null cochlear hair cells expressing TMC1 variants demonstrate that alterations within this loop affect channel activation, identifying it as a modulatory feature that has been refined through structural adaptation.

  PublisherDOI

• Mini-Pcdh15b Gene Therapy Rescues Visual Deficits in a Zebrafish Model of Usher Syndrome Type 1F

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-06

  preprint

  ABSTRACT Usher syndrome type 1F (USH1F) is a severe inherited disorder caused by mutations in PCDH15 , resulting in congenital deafness, vestibular dysfunction, and progressive retinal degeneration leading to blindness. While cochlear implantation can restore hearing, no therapeutic interventions currently exist for vision loss. Gene augmentation therapy represents a promising approach; however, the PCDH15 coding sequence (∼5.3 kb) exceeds the packaging capacity of adeno-associated virus (AAV) vectors. To overcome this limitation, we previously engineered shortened “mini-PCDH15” constructs that retain key structural and functional domains while fitting within a single AAV. Among these, the mini-PCDH15-V4 variant successfully restored hearing in Pcdh15 -deficient mice. Here, we investigated the ability of a cone-targeted mini-pcdh15b-V4 transgene to rescue vision in a zebrafish model of USH1F. Untreated pcdh15b -deficient zebrafish exhibited severe structural and functional defects of the retina, including disorganized and shortened photoreceptor outer segments, disrupted calyceal processes, and markedly reduced electroretinogram (ERG) and optokinetic response (OKR) performance. Targeted expression of mini- pcdh15b -V4 recapitulated typical localization of Pcdh15b to calyceal processes and outer segment membranes, rescued photoreceptor architecture, and re-established both structural organization and functional output. Treated mutants exhibited improved visual tracking behavior and full recovery of ERG a-wave and b-wave amplitudes, indicating restoration of photoreceptor and synaptic function. Importantly, mini- pcdh15b -V4 expression produced no adverse effects in wild-type or heterozygous fish, supporting the safety of cone-specific expression. Together, these findings demonstrate that mini- pcdh15b -V4 can restore both photoreceptor structure and visual function in pcdh15b -deficient zebrafish. This work establishes the pcdh15b mutant zebrafish as a powerful preclinical model for studying USH1F retinopathy and supports the translational potential of rationally engineered mini-PCDH15 constructs as a feasible gene therapy approach for preventing or reversing vision loss in individuals with USH1F.

  PublisherDOI

• Small Molecule Inhibition of CPSF3 Impacts R-Loop Distribution and Abundance

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access1st authorCorresponding
  PublisherDOI

• Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea

  Nature Communications · 2025-12-16 · 1 citations

  articleOpen accessSenior author

  Mutations in the GJB2 gene cause DFNB1, the most common hereditary hearing loss. GJB2 is expressed by cochlear epithelial cells and fibrocytes, but not by sensory hair cells or neurons. Attempts to treat DFNB1 mouse models with gene therapy have not substantially restored function, as inappropriate expression in hair cells and neurons might compromise their electrical activity. Here, we use ATAC-seq to identify candidate gene regulatory elements (GREs) that can drive cell-type-specific expression of GJB2. HA-tagged GJB2, delivered to a conditional knockout mouse with AAV vectors carrying GREs, is expressed by the appropriate cells, prevents degeneration, and rescues hearing by only 10-20 dB. In a Gjb2 partial knockdown model, a vector lacking HA prevents degeneration and completely restores hearing. In cynomolgus monkey cochleas, human GJB2.HA delivered with similar vectors is located in the appropriate cell types and causes little or no compromise of hearing sensitivity. Together, these findings suggest that GRE-mediated expression of GJB2 can prevent hearing loss in DFNB1 patients.

  PublisherDOI

• Elasticity and Thermal Stability are Key Determinants of Hearing Rescue by Mini-Protocadherin-15 Proteins

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-17

  preprintOpen access

  Protocadherin-15 is a core protein component of inner-ear hair-cell tip links pulling on transduction channels essential for hearing and balance. Protocadherin-15 defects can result in non-syndromic deafness or Usher syndrome type 1F (USH1F) with hearing loss, balance deficits, and progressive blindness. Three rationally engineered shortened versions of protocadherin-15 (mini-PCDH15s) amenable for gene therapy have been used to rescue function in USH1F mouse models. Two can successfully or partially rescue hearing, while another one fails. Here we show that despite varying levels of hearing rescue, all three mini-PCDH15 versions can rescue hair-cell mechanotransduction. Negative-stain electron microscopy shows that all three versions form dimers like the wild-type protein, while crystal structures of some engineered fragments show that these can properly fold and bind calcium ions essential for function. In contrast, simulations predict distinct elasticities and nano differential scanning fluorimetry shows differences in melting temperature measurements. Our data suggest that elasticity and thermal stability are key determinants of sustained hearing rescue by mini-PCDH15s.

  PublisherOA PDFDOI

• In silico mechanics of mini-PCDH15 proteins rationally designed for inner-ear gene therapy

  Biophysical Journal · 2024-02-01

  articleOpen access
  PublisherOA PDFDOI

• The auditory midbrain mediates tactile vibration sensing

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-08 · 2 citations

  preprintOpen access

  Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body's Pacinian corpuscle neurons, which are unique in their ability to entrain to high frequency (40-1000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

  PublisherOA PDFDOI

• PCDH15 dual-AAV gene therapy for deafness and blindness in Usher syndrome type 1F models

  Journal of Clinical Investigation · 2024-10-23 · 23 citations

  articleOpen accessSenior author

  Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual-adeno-associated virus (dual-AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and nonhuman primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

  PublisherOA PDFDOI

• Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-24 · 5 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Mutations in the GJB2 gene cause the most common form of human hereditary hearing loss, known as DFNB1. GJB2 is expressed in two cell groups of the cochlea—epithelial cells of the organ of Corti and fibrocytes of the inner sulcus and lateral wall—but not by sensory hair cells or neurons. Attempts to treat mouse models of DFNB1 with AAV vectors mediating nonspecific Gjb2 expression have not substantially restored function, perhaps because inappropriate expression in hair cells and neurons could compromise their electrical activity. Here, we used genomic chromatin accessibility profiling to identify candidate gene regulatory elements (GREs) that could drive cell-type-specific expression of Gjb2 in the cochlea. HA-tagged GJB2, delivered to a conditional knockout model in an AAV vector with GRE control of expression, was localized to the appropriate cell types, prevented the cochlear degeneration observed in untreated knockout mice, and partially rescued hearing sensitivity. In a Gjb2 partial knockdown mouse model, such exogenous GJB2 prevented degeneration and completely restored hearing sensitivity. We tested control of expression by these GREs in nonhuman primate cochleas and found that vector-delivered human GJB2.HA was located in the appropriate cell types and caused little or no reduction in hearing sensitivity. Together, these findings suggest that GRE-mediated expression of GJB2 could prevent hearing loss in DFNB1 patients.

  PublisherOA PDFDOI

• The auditory midbrain mediates tactile vibration sensing

  Cell · 2024-12-18 · 19 citations

  articleOpen access

  Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body's Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40-1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

  PublisherDOI

Recent grants

• NIH Grant R01DC002281

  NIH · $5.5M · 2020

• HMS/BCH Center for Neuroscience Research

  NIH · $11.6M · 2011–2022

• Molecular Mechanisms of Auditory Transduction

  NIH · $11.0M · 1984–2028

• NIH Grant R01NS022059

  NIH · $178k · 1988

• Development of Gene Therapy for Hereditary Deafness using Rational Protein Engineering

  NIH · $2.6M · 2022–2027

Frequent coauthors

• Jaime Garcı́a-Añoveros

  Knowles (United States)

  108 shared

• Zheng‐Yi Chen

  Harvard University

  99 shared

• Melissa A. Vollrath

  McGill University

  73 shared

• Cyrille Sage

  Howard Hughes Medical Institute

  64 shared

• Jeffrey R. Holt

  Harvard University

  62 shared

• Duan-Sun Zhang

  Howard Hughes Medical Institute

  57 shared

• Peter G. Gillespie

  Oregon Health & Science University

  55 shared

• Mingqian Huang

  Harvard University

  54 shared

Labs

• COREY LABORATORYPI

Education

• Ph.D., Neuroscience

  Harvard University

  1990

• B.S., Biology

  University of California, San Diego

  1985