Characterization of AAV-mediated dorsal root ganglionopathy

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates

“…The mechanism responsible for histopathologic findings observed in the NHP study is unknown but could be associated with high transgene expression in sensory neurons. 31 DRG neurons are highly transduced after intra-CSF delivery of AAV vectors, 25 , 26 a finding confirmed in our NHP study with up to 4.9 × 10 6 vg/μg of DNA and up to 2.3 × 10 8 vg/μg of RNA found in high-dose LYS-GM101 treated animals. Interestingly, no vector-related histopathology was apparent in spinal cord, DRG, and sciatic nerve sections from GM1 gangliosidosis cats 10 months after treatment with the feline analog of LYS-GM101 via the i.c.m.…”

Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates

“…No increases in NfL were observed within a 28-day post-dose observation period after administration of empty AAV9 capsid and scAAV9 containing a promoter-less transgene, consistent with the subsequent lack of DRG degeneration, necrosis, and/or loss, supporting the supposition that the pathogenesis of the AAV-related DRG injury and inflammation is driven by increased transgene expression regulated by the promoter used. 26 , 27 …”

Society of Toxicologic Pathology Neuropathology Interest Group Article: Neuropathologic Findings in Nonhuman Primates Associated With Administration of Biomolecule-Based Test Articles

“…94 However, modest degrees of neuronal necrosis in DRG that occur as a class effect following AAV administration typically do not produce in-life neurological signs or consistent electrophysiological deficits. 70,71,73 Therefore, visible structural effects that do not elicit biologically significant functional disturbances support the continued development of biologic candidates that elicit some degree of unavoidable neuropathology for treating severe neurological diseases with few or no current effective therapeutic options.…”

“…By definition, degeneration is a potentially reversible disturbance in neuronal function, while necrosis is an irreversible event that culminates in cell death. The pathogenetic mechanisms likely resulting in both of these changes may involve direct toxicity of the biomolecule (e.g., an overexpressed human protein) toward the neuron 70,71 or an immune response mounted against a molecular target that is present within the nervous system. 72 Features of neuronal degeneration may include cytoplasmic pallor due to variable dispersal of Nissl substance (RNA-rich rough endoplasmic reticulum), vacuolation at the cell periphery, and often nuclear chromatin margination and/or loss of the nucleolus.…”