Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology

Area of Science:

• Neuroscience
• Toxicology
• Gene Therapy

Background:

• Adeno-associated virus (AAV) vectors are widely used in gene therapy.
• Administration of AAV vectors can lead to dorsal root ganglion (DRG) pathology in nonhuman primates (NHP).
• Understanding the factors influencing DRG pathology is crucial for AAV-based therapeutic development.

Purpose of the Study:

• To perform a meta-analysis on the severity of DRG pathology following AAV administration in NHP.
• To identify factors influencing DRG pathology, including route of administration, dose, age, sex, capsid, promoter, purification, and transgene.
• To assess the clinical relevance and time course of AAV-induced DRG pathology.

Main Methods:

• Meta-analysis of data from 33 nonclinical studies involving 256 NHP.
• Comparison of DRG pathology severity across various administration routes (CSF vs. intravenous - IV).
• Statistical analysis to determine the impact of dose, age, sex, vector components, and time post-injection on pathology.

Main Results:

• DRG pathology observed in 83% of NHP receiving AAV via CSF and 32% via IV injection.
• Dose and age at injection were significant factors affecting pathology severity; sex had no impact.
• Pathology was minimal at acute time points (<14 days), stable from 1-5 months, and reduced after 6 months; vector purification method, capsid, promoter, and transgene did not significantly alter occurrence.

Conclusions:

• DRG pathology is a common finding in NHP following AAV gene therapy, irrespective of vector components.
• While often subclinical, DRG pathology can be detected by sensitive functional tests.
• Monitoring for sensory neuropathies in human clinical trials, especially high-dose IV studies, is recommended.