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SPLICE CORRECTION WITH ANTISENSE OLIGONUCLEOTIDES AS A THERAPEUTIC APPROACH FOR NIEMANN–PICK TYPE C1 DISEASE
Maria Martinez de Lagranand 8 co-authors
Centre for Genomic Regulation
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-067
Presentation
Date TBA
Board: PS06-09PM-067
Event Information
Poster Board
PS06-09PM-067
Poster
View posterAbstract
Niemann-Pick disease type C1 is a fatal, inherited neurovisceral heterogenous disorder caused by mutations in the NPC1 gene, involved in lysosomal cholesterol transport. The disease is characterized by infantile cholestasis, neurodegeneration with variable age of onset and psychiatric symptoms in older patients. Mortality primarily results from central nervous system dysfunction and there are currently no curative treatments. To develop a targeted gene-based therapeutic strategy, we have assessed the efficacy of a panel of novel synthetic splice-switching oligonucleotides (SSOs) in a murine model carrying the NPC1 c.1554-1009G>A pseudoexon-generating mutation.
First, we conducted in vitro screening of a panel of SSOs in patient-derived fibroblast cultures, using established 2′-MOE/PS chemistry alongside a novel thiomorpholino chemistry. Several SSOs recovered normal splicing, suppressing NPC1 pseudo-exon inclusion and achieving functional rescue. Selected SSOs were subsequently intracerebroventricularly injected to the NPC1 murine model at postnatal day 1-2. At 6 weeks post-injection, mice were submitted to a comprehensive battery of behavioral assays assessing motor and cognitive function. Although dose-dependent toxicity was observed at higher concentrations, low-dose SSO administration resulted in a partial rescue of cognitive deficits, as assessed by the object recognition test, as well as improved motor performance in the rotarod and balance beam assays.
Our results support the clinical applicability of antisense therapy for Niemann–Pick disease type C1, representing a critical first step toward clinical translation.
First, we conducted in vitro screening of a panel of SSOs in patient-derived fibroblast cultures, using established 2′-MOE/PS chemistry alongside a novel thiomorpholino chemistry. Several SSOs recovered normal splicing, suppressing NPC1 pseudo-exon inclusion and achieving functional rescue. Selected SSOs were subsequently intracerebroventricularly injected to the NPC1 murine model at postnatal day 1-2. At 6 weeks post-injection, mice were submitted to a comprehensive battery of behavioral assays assessing motor and cognitive function. Although dose-dependent toxicity was observed at higher concentrations, low-dose SSO administration resulted in a partial rescue of cognitive deficits, as assessed by the object recognition test, as well as improved motor performance in the rotarod and balance beam assays.
Our results support the clinical applicability of antisense therapy for Niemann–Pick disease type C1, representing a critical first step toward clinical translation.
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