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Head to head comparison of target knockdown following OTV vs. anti-TfR:ASO administration in mice

ABSTRACT: Using single nucleus RNA sequencing, we determined that peripheral administration of OTV:Malat1 results in much more widespread and robust target knockdown throughout the mouse brain compared to anti-TfR:Malat1.

ORGANISM(S): Mus musculus

PROVIDER: GSE201787 | GEO | 2024/02/12

REPOSITORIES: GEO

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A Biodistribution Study of OTV vs. ASO by Intravenous or Intrathecal Administration in Cynomolgus Monkeys

Project description:The objective of this study is to evaluate ASO biodistribution and pharmacodynamic response following intravenous delivery of conjugated OTV, which utilizes transferrin-receptor binding to deliver ASO, vs. intrathecal delivery of naked ASO in cynomolgus monkeys, the current gold standard for ASO delivery. Three groups were included for comparison: 1) Negative control cohort = Four biweekly intravenous doses of saline (n=3); 2) IT cohort = Single intrathecal dose of 4mg MALAT1 ASO (n=3); 3)  OTV multi dose cohort = Four biweekly intravenous doses of 30mpk OTV:MALAT1 (n=3). Tissues were collected two weeks after the final dose to allow sufficient time for target knockdown. Brain, spinal cord, and peripheral tissues were dissected and frozen for molecular analysis. Compared to an intrathecal injection of ASO, systemic administration of OTV resulted in significantly more homogenous biodistribution of ASO in the central nervous system as measured by a probe-based hybridization assay as well as staining with an anti-ASO antibody. One potential consequence of heterogeneous ASO distribution is heterogeneous target knockdown throughout the CNS. We observed more consistent target knockdown throughout the cortex, subcortical areas, and spinal cord of monkeys dosed peripherally with OTV. By contrast, monkeys dosed intrathecally with naked ASO showed much more knockdown in the spinal cord compared to the brian, consistent with ASO distribution.

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Target knockdown after systemic OTV administration in mice

Project description:Using single nucleus RNA sequencing, we knockdown of Malat1 across all cell types upon peripheral administration of OTV:Malat1.

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