CSF Infusion of Gene Therapy Transduces Cochlear Cells


The most robust transduction in nonhuman primates was seen with ICV delivery of pooled PM4.AAV.mRFP and AAV2.mNG gene therapy,

New research has validated the use of cerebrospinal fluid (CSF)-mediated delivery for adeno-associated virus (AAV) gene transfer to the primate cochlea and may support the future use of targeted gene therapy to cells relevant to hearing loss without middle ear surgery.

The research was presented at the late-breaking session at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by Paul T. Ranum, PhD, postdoctoral fellow, data scientist and molecular biologist, The Children's Hospital of Philadelphia.

“Essentially what we found is that when AAV is infused into the CSF in non-human primates it’s capable of yielding potent cochlear transduction... This is the organ responsible for hearing function, and inside the cochlea, AAV is capable of transducing the key sensory cells involved in hearing, the auditory or hair cells. This is noteworthy because current efforts to deliver gene therapy to the inner ear involve direct infusion of AAV via middle ear surgery… so this presents totally different approach to delivering AAVs to the inner ear,” Ranum said during his presentation. “The temporal bone is one of the most dense bones in the body and this is probably why not many other groups are looking at cochlear transduction for their central nervous system (CNS) distribution assays.”

READ MORE: Otoferlin-Related Hearing Loss Gene Therapy DB-OTO Cleared for Clinical Trial Expansion to Spain

Ranum and colleagues evaluated temporal bones from a study of capsid distribution in the CNS of non-human primatesby whole mount microdissection and fluorescence imaging and found robust CSF-mediated transduction of inner hair cells (IHCs) at the apex of the cochlea. They then performed and evaluated transduction with intracerebroventricular (ICV) and intracochlear infusions of candidate AAVs, including AAV9.EGFP, PM1.AAV9.mNG, PM2.AAV1.mNG, PM3.AAV2.mTFP, and a pooled PM4.AAV.mRFP and AAV2.mNG gene therapies, the latter of which yielded robust transduction of spiral ganglion neurons in addition to transduction of IHCs and outer HCs.

“In summary, we’veidentified a highly effectivenew route of administration of AAV to the inner ear through the CSF, we’veidentified next generation AAV capsids that are capable of transducing many auditory cell types, and we’ve shown that our PM2 candidate is capable of outperforming a standard gene therapy in nonhuman primates when it’s administrated by CSF delivery. This new approach offers a lot ofopportunities. The first is that it doesn’tinvolve middle ear surgery and this is key because without the requirement of middle ear surgery, it’s possible to begin to think about earlier administration and this is a critical advantage for congenital, rapid, progressive hearing loss. This methodology also enables us to utilize capsid screening to identify additional modified capsids that may be capable of targeting other high volume cochlear cell types," Ranum concluded.

Click here to read more coverage of ASGCT 2023.

Ranum PT, Tecedor L, Keiser MS, et al. Cerebrospinal Fluid Enables Potent AAV Gene Delivery to the Primate Inner Ear. Presented at: ASGCT 2023 Annual Meeting; May 16-20; Los Angeles, California.
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