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Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration.

Abstract：

:Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that influence AAV distribution in the CSF so that optimal parameters can be replicated in the clinic. In the context of developing a motor neuron-targeted gene therapy for spinal muscular atrophy, we conducted studies in nonhuman primates to evaluate the impact of injection volume on spinal cord transduction after AAV delivery via lumbar puncture. Lumbar injection of an AAVhu68 vector targeted motor neurons throughout the spinal cord, but only in juvenile nonhuman primates administered large injection volumes, equivalent to about half of the total CSF volume. Upon repeating this study with clinically relevant injection volumes and larger animals, we found that lumbar puncture failed to achieve significant transduction of the spinal cord. In contrast, vector administered into the cisterna magna distributed reproducibly throughout the spinal cord in both juvenile and adult animals. These findings highlight the challenges of translating AAV delivery via lumbar puncture to humans and suggest that delivery into the cisterna magna may represent a more feasible alternative.

journal_name

Mol Ther Methods Clin Dev

journal_title

Molecular therapy. Methods & clinical development

authors

Hinderer C,Katz N,Dyer C,Goode T,Johansson J,Bell P,Richman L,Buza E,Wilson JM

doi

10.1016/j.omtm.2020.04.012

subject

Has Abstract

pub_date

2020-04-18 00:00:00

pages

969-974

issn

2329-0501

pii

S2329-0501(20)30072-3

journal_volume

17

pub_type

杂志文章

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