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De-risking ASO-induced histopathology in spinal cord of monkeys by molecular localization investigations

Nunes, Jairo, Dubost, Valerie, Wuersch, Kuno, Penraat, Kelley and Balavenkatraman, Kamal Kumar (2024) De-risking ASO-induced histopathology in spinal cord of monkeys by molecular localization investigations. Toxicologic pathology.


The safety of a 2′-O-methoxyethyl antisense oligonucleotide (2'-MOE ASO) was investigated in cynomolgus monkeys in a chronic toxicity study after repeated intrathecal (IT) administration. Histopathological examination revealed formation of lymphoid follicles in the spinal cord (SC) at the injection site and presence of granular material in motor neurons of the SC in high dose animals. The granular material was seen in all the segments of the SC, but mainly in the lumbar segment and persisted at recovery. Findings associated with repeated intrathecal administration of 2' MOE ASOs have been characterized in non-human primate toxicity studies, especially in the brain but findings in the SC are poorly documented. We reported a high incidence of findings in the SC compared to brain, especially in the lumbar segment in proximity with IT injection sites. An extensive panel of immunohistochemistry (IHC) markers showed that the lymphoid follicles had a cellular composition and organization consistent with a tertiary lymphoid structure (TLS) and were not associated with axonal damage in the adjacent nervous tissue. IHC markers of neuronal degeneration and function, in additional to ISH with a miRNA probe complementary to the ASO revealed that the granular material was composed of a dose proportional ASO accumulation in the cytoplasm of neurons without inducing cell death or apoptosis but perturbing the lysosomal trafficking. Glial and ependymal cells in the SC also showed dose dependent ASO accumulation in the absence of granular material noted by H&E. Based on these molecular localization data, the presence of lymphoid follicles in SC suggests a chronic local immune activation due to repetitive IT injections of ASO and the granular material in SC neurons were caused by ASO accumulation. Based on the lack of cellular dysfunction or axonal damage, these findings were considered as non-adverse.

Item Type: Article
Date Deposited: 13 Feb 2024 00:46
Last Modified: 13 Feb 2024 00:46