Toxicology Study of Intra-Cisterna Magna Adeno-Associated Virus 9 Expressing Iduronate-2-Sulfatase in Rhesus Macaques

Abstract

Hunter syndrome is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. The severe form of this progressive, systemic, and neurodegenerative disease results in loss of cognitive skills and early death. Several clinical trials are evaluating adeno-associated virus 9 for the treatment of neurodegenerative diseases using systemic or intrathecal lumbar administration. In large animals, administration via suboccipital puncture gives better brain transduction than lumbar administration. Here, we conducted a good laboratory practice-compliant investigational new drug-enabling study to determine the safety of suboccipital adeno-associated virus 9 gene transfer of human iduronate-2-sulfatase into nonhuman primates. Thirteen rhesus macaques received vehicle or one of two doses of vector with or without immunosuppression. We assessed in-life safety and immune responses. Animals were euthanized 90 days post-administration and sampled for histopathology and biodistribution. The procedure was well tolerated in all animals. Minimal mononuclear cerebrospinal fluid pleocytosis occurred in some animals. Asymptomatic minimal-to-moderate toxicity to some dorsal root ganglia sensory neurons and their associated axons occurred in all vector-treated animals. This study supports the clinical development of suboccipital adeno-associated virus 9 delivery for severe Hunter syndrome and highlights a potential toxicity that warrants monitoring in first-in-human studies.

Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology

“…GENE THERAPY USING recombinant adeno-associated virus (AAV) has been linked with histopathological findings in dorsal root ganglion (DRG) sensory neurons in preclinical studies using nonhuman primates 1 and pigs. 2 The pathology manifests as mononuclear cell infiltrates and sensory neuron degeneration within the DRG in addition to secondary axonopathy, which affects both the central axon of dorsal spinal cord (SC) tracts and the peripheral axon of peripheral nerves (Fig.…”

Adeno‐associated virus serotype 1‐based gene therapy for FTD caused by GRN mutations

“…Our findings were similar to previous ICM AAV studies. 25,26 We observed occasional, minimal lymphocytic infiltrates in the meninges and choroid plexus as well as degeneration of sensory neurons and their associated axons in some dorsal root ganglia and spinal cord sections (Fig. S3).…”

“…These findings were consistent with previous ICM AAV studies and were not associated with clinical signs. 21,25,26 No vector-related abnormalities were noted in the brain parenchyma of any of the AAV1-or AAVhu68-treated animals.…”

Gene and Cell-Based Therapies for Parkinson's Disease: Where Are We?

“…However, it is also possible that the AAV9 serotype is particularly susceptible to detrimental side effects under certain delivery conditions, possibly because of its ability to transfect a wide variety of cells types. Thus, intravenous and intracisternal delivery in animal models has been reported to cause a sensory neuronopathy of variable severity [ 28 , 31 , 32 ]. Interestingly, Perez et al report that use of species-specific transgene may prevent this outcome, implying that an anti-transgene immune response may contribute in some cases, but autoimmune and toxic causes have also been speculated [ 28 , 32 ].…”

“…Thus, intravenous and intracisternal delivery in animal models has been reported to cause a sensory neuronopathy of variable severity [ 28 , 31 , 32 ]. Interestingly, Perez et al report that use of species-specific transgene may prevent this outcome, implying that an anti-transgene immune response may contribute in some cases, but autoimmune and toxic causes have also been speculated [ 28 , 32 ]. The reports have been concerning enough to put a halt to further use of the intrathecal route for delivery of Zolgensma (AAV9) for spinal muscular atrophy—a treatment that received licensing for human use (intravenously) in 2019 [ 33 , 34 ].…”