Abstracts

Rationale: Regulatory RNAs (regRNAs), including enhancer RNAs, promoter-associated RNAs and Natural Antisense Transcripts (NAT) are key regulators of mRNA transcription. We have developed a platform that enables us to design antisense oligonucleotides (ASOs) against relevant regRNAs to modulate the expression of cognate genes as a therapeutic approach for a wide range of haploinsufficient and deficiency disorders. Dravet syndrome (DS) is a prototypical developmental encephalopathy, which is caused by haploinsufficiency of SCN1a in approximately 80% of DS patients. Expression of SCN1A is regulated by SCN1A-NAT. We have previously shown that targeting SCN1A-NAT by an ASO can upregulate the expression of SCN1A in vitro and in vivo leading to significant reductions in seizures. Here, we report our recent results measuring the efficacy and duration of action of CMP-SCN-001 in non human primates (NHP).

Methods: We have conducted pharmacodynamic studies in NHP following intrathecal administration CMP-SCN-001 to investigate distribution and efficacy over time in different regions within the central nervous system (CNS).

Results: We have observed wide distribution of CMP-SCN-001 within the CNS as well as positive pharmacodynamic effects on SCN1A expression at both the mRNA and protein levels. We have also gained valuable insight into the duration of action of CMP-SCN-001.

Conclusions: We have shown that ASO targeting of SCN1A-NAT is a viable therapeutic approach for Dravet Syndrome, and we are advancing a lead ASO into clinical testing. Our findings will inform the design of IND-enabling GLP tox studies with CMP-SCN-001 targeting human SCN1A-NAT.

Funding: Private investor funding