Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration

Christian Hinderer,Nathan Katz,Cecilia Dyer,Tamara Goode,Julia Johansson,Peter Bell,Laura Richman,Elizabeth Buza,James M Wilson

doi:10.1016/j.omtm.2020.04.012

Christian Hinderer, Nathan Katz + Show 7 more

Open Access

https://doi.org/10.1016/j.omtm.2020.04.012

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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.

Highlights

When we performed the same comparison in adult animals, only intra-cisterna magna (ICM) delivery resulted in significant motor neuron transduction
We previously reported that lumbar puncture is far less effective than ICM associated virus (AAV) administration in nonhuman primates (NHPs),[8] here we were able to reproduce the successful gene transfer to the spinal cord reported by another group by more closely replicating aspects of their model system and injection method
Following ICM AAV administration, we consistently observed a lumbar-to-cervical gradient of motor neuron transduction despite the greater distance from the lumbar region to the injection site

Summary

INTRODUCTION

Adeno-associated virus (AAV)-mediated gene transfer has demonstrated the potential for long-term expression of a transgene in the human brain with an acceptable safety profile.[1,2,3] Most evidence of persistent gene transfer has been limited to clinical trials in which the vector was injected directly into the brain parenchyma.[1,2,3] this approach is promising for some diseases, intraparenchymal injection is an invasive procedure that results in limited distribution of the vector beyond the injection site, making it unsuitable for many applications.[3,4] Expanding the potential of AAV gene therapy to new targets will require the identification of capsids and delivery methods that can broadly target cells relevant to each disease. In large-animal studies, transduction of the lower motor neurons has been demonstrated after AAV delivery into the CSF via the lateral cerebral ventricles, cisterna magna, or lumbar cistern.[8,12] Injection via lumbar puncture has clear advantages given that this is a widely used approach in clinical practice. An AAV vector from a lumbar puncture to determine whether changes to the procedure could allow a lumbar intrathecal approach to be translated to humans

RESULTS

DISCUSSION

MATERIALS AND METHODS