B6 - Ophthalmic and Auditory Diseases
85: Cochlear Gene Therapy Delivery Innovations, AAV Capsid Variants and Cell Type-Specific Regulatory Elements to Facilitate CSF-Mediated Administration
Type: Oral Abstract Session
Presentation Details
Session Title: Ophthalmic and Auditory: Delivery Innovations
The recent clinical success of AK-OTOF has demonstrated the feasibility and value of gene therapies for hearing and deafness. Current approaches to cochlear gene therapy use AAV intracochlear infusion via an inner ear surgical approach. This method necessitates general anesthesia, perforation(s) of the sealed inner ear space, and patients of sufficient age to facilitate the approach. However, the complexity of the auditory system and extreme diversity of genetic causes of hearing loss remain barriers to broader targeting of most hearing loss genes. Delivery continues to pose challenges at every level: the therapeutic window of opportunity, the vectors to target various hearing-relevant cochlear cell types, and payload design that limit expression to therapeutically relevant cells. Toward these goals we used our recently developed cerebrospinal fluid (CSF)-mediated route of gene therapy administration to the inner ear and round window membrane + canalostomy (RWM) infusions of WT and modified AAVs into NHPs to identify new hearing-relevant AAV capsids that target primate cochlear cells and developed a pipeline for splicing-based regulatory element discovery with validation in murine auditory inner hair cells (IHCs).
CSF-mediated delivery of our top modified AAV variants yielded capsids capable of nearly complete IHC transduction across all cochlear turns, robust transduction of spiral ganglion neurons, and transduction of non-sensory supporting cells in the organ of Corti of the NHP cochlea. Additionally, using available single-cell RNA-Seq data, we tested a hair-cell-specific splice event with 100% sequence conservation between mouse and human for its ability to confer hair cell-specific payload expression. After ICV administration to mouse CSF there was auditory hair cell specific gene expression, and no expression throughout the non-cochlear central nervous system.
In summary, we show an alternative method for gene delivery to the inner ear via the CSF, identified new capsid variants for cochlear gene delivery, and developed regulatory elements to limit gene expression to a cochlear cell-type of interest, all steps towards further development of gene therapies for hearing loss.
Plain Language Summary
Despite recent success in the field, gene therapy design and delivery to the inner ear remains a challenge. Here we report progress toward characterization of AAV capsid variants and cell-type-specific regulatory elements that are enabling for development of new therapeutic approaches targeting hearing loss.
Paul T. Ranum1, Ellie Carrell2, Jenna Devare3, Luis Tecedor2, Yonghong Chen2, Ryan Giovenco2, Alejandro Mas Monteys4, Stephen R. Chorney5, Robert C. O'Reilly5, Beverly L. Davidson2
1Latus Bio, Philadelphia, PA,2Children's Hospital of Philadelphia, Philadelphia, PA,3The Children's Hospital of Philadelphia, Philadelphia, PA,4University of Pennsylvania, Philadelphia, PA,5Division of Pediatric Otolaryngology, Children’s Hospital of Philadelphia, Philadelphia, PA"
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