Tukov, Francis, Mansfield, Keith, Milton, Mark, Meseck, Emily, Penraat, Kelley, Hartmann, Andreas and Chand, Deepa (2022) Single-Dose Intrathecal Dorsal Root Ganglia Toxicity of Onasemnogene Abeparvovec in Cynomolgus Monkeys. Human gene therapy. ISSN 1557-7422

Abstract

Intravenous onasemnogene abeparvovec is approved for spinal muscular atrophy in children <2 years. For later-onset patients, intrathecal onasemnogene abeparvovec may be advantageous over intravenous administration. Recently, microscopic dorsal root ganglion (DRG) changes were observed in nonhuman primates (NHPs) following intrathecal onasemnogene abeparvovec administration. To characterize these DRG findings, two NHP studies evaluating intrathecal onasemnogene abeparvovec administration were conducted: a 12-month study with a 6-week interim cohort and a 13-week study with a 2-week interim cohort. The latter investigated the potential impact of prednisolone or rituximab plus everolimus on DRG toxicity. An additional 6-month, single-dose, intravenous NHP study conducted in parallel evaluated onasemnogene abeparvovec safety (including DRG toxicity) with or without prednisolone co-administration. Intrathecal onasemnogene abeparvovec administration was well-tolerated and not associated with clinical observations. Microscopic onasemnogene abeparvovec-related changes were observed in the DRG and trigeminal ganglion (TG) and included mononuclear cell inflammation and/or neuronal degeneration, which was colocalized with high vector transcript expression at 6 weeks post-dose. Incidence and severity of DRG changes were generally decreased after 52 weeks compared with 6 weeks post-dose. Other onasemnogene abeparvovec-related microscopic findings of axonal degeneration, mononuclear cell infiltrates and/or gliosis in the spinal cord, dorsal spinal nerve root/spinal nerves, and/or peripheral nerves were absent or found at decreased incidences and/or severities after 52 weeks. DRG and/or TG microscopic findings following intravenous onasemnogene abeparvovec dosing included minimal to slight neuronal degeneration and mononuclear cell inflammation at 6 weeks and 6 months post-dose. Nervous system microscopic findings following intrathecal onasemnogene abeparvovec (≥1.2×1013 vg/animal) trended toward resolution after 52 weeks, supporting non-progression of changes, including in the DRG. Onasemnogene abeparvovec-related DRG findings were not associated with electrophysiology changes and were not ameliorated by prednisolone or rituximab plus everolimus co-administration. The pathogenesis is possibly a consequence of increased vector genome transduction and/or transgene expression.

Item Type:	Article
Date Deposited:	26 Jul 2022 00:45
Last Modified:	26 Jul 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46057