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A - Viral Vector Development -> AAV Vectors – Clinical/Non-Human Primate Studies

Cerebrospinal Fluid Enables Potent AAV Gene Delivery to the Primate Inner Ear

Type: Oral Abstract Session

Presentation Details
Session Title: Late-breaking Abstracts 2
Location: Concourse Hall 152 & 153
Start Time: 5/19/2023 11:15
End Time: 5/19/2023 11:30

Hearing loss is among the most challenging genetic disorders to correct with gene therapy. Therapeutic delivery is impeded by temporal bone and cochlear anatomy, while payload design and capsid choice is complicated by a high diversity of genetic lesions impacting a range of functionally critical cell types. Despite these challenges, a growing number of gene therapy approaches have been designed and validated in murine models of hearing loss. However, anatomical and cellular variation between mice and primates has slowed translation of these therapies to humans. Many capsids that work in mice do not perform well in primates and current delivery approaches require middle ear surgery and multiple perforations of the sealed cochlear space. To overcome these challenges and expand the number of hearing loss genes for which gene therapies can be developed we leveraged ongoing parallel studies of AAV tropism in the central nervous system. This cross-discipline work in primates has identified new capsids and routes of administration relevant to cochlear gene therapy.
Here, we took advantage of temporal bones from a study of capsid distribution in the central nervous system and evaluated them by whole mount microdissection and fluorescence imaging. AAV administration to non-human primates in this study was performed by intracerebroventricular (ICV) infusion of candidate AAVs into the cerebrospinal fluid (CSF). Our initial observations showed robust CSF-mediated transduction of Inner hair cells (IHCs) at the apex of the cochlea from a rhesus macaque that received ICV infusion AAV9.EGFP or a peptide modified variant, PM1.AAV9.mNG. There was greater IHC transduction in the middle and basal turns of the cochlea with PM1.AAV9 vs wildtype AAV9.
PM1.AAV9.mNG was also assessed following direct intracochlear delivery using the standard trans-round window membrane infusion + canalostomy in NHPs. Interestingly, direct intracochlear infusion yielded improved transduction of IHCs in the middle turn but inferior IHC transduction in the apex and base relative to ICV delivery.
Next, we evaluated cochlear transduction from a primate that received ICV infusion of a pool of peptide modified AAVs based on AAV1, AAV2 and compared them to wild type AAV9. Both PM2.AAV1.mNG and PM3.AAV2.mTFP yielded nearly complete transduction of inner hair cells and robust transduction of other cochlear cell types throughout all cochlear turns. This transduction pattern was confirmed with fluorophore-specific FISH. Finally, in cochlea from a primate that received pooled PM4.AAV.mRFP and AAV2.mNG there was striking transduction of spiral ganglion neurons in addition to transduction of IHCs and OHCs.
Taken together, these results highlight the utility of CSF-mediated delivery for AAV gene transfer to the primate cochlea. When combined with peptide modified AAV capsids this approach can achieve robust gene delivery to many hearing loss relevant cell types and can transduce all cochlear turns. Furthermore, because ICV delivery does not require middle ear surgery, it may enable gene therapy delivery at earlier timepoints which may be required to prevent some forms of rapidly progressive and congenital sensorineural hearing loss.

Paul T. Ranum1, Luis Tecedor1, Megan S. Keiser1, Yonghong Chen1, Stephen R. Chorney2, Xueyuan Liu3, Robert C. O’Reilly2, Beverly L. Davidson1

1Children's Hospital of Philadelphia, Philadelphia, PA,2Pediatric Otolaryngology, Children's Hospital of Philadelphia, Philadelphia, PA,3The Children's Hospital of Philadelphia, Philadelphia, PA
 P.T. Ranum: None.

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