Description
The abstract mentions ASO targeting of gene transcripts but doesn’t explain how these therapeutics distinguish between disease-causing expanded CAG repeats and normal alleles. This selectivity is crucial for therapeutic safety and efficacy in treating polyQ disorders.
Gap type: unexplained_observation Source paper: Antisense oligonucleotide therapeutics in neurodegenerative diseases: the case of polyglutamine disorders. (2020, Brain : a journal of neurology, PMID:31738395)
Resolution criteria
Resolved when mutant-versus-wild-type allele selectivity rules for polyQ ASOs are quantified. Required evidence: ASO panels tested against expanded and normal CAG alleles, transcript knockdown by allele-specific qPCR or long-read RNA sequencing, mismatch/repeat-length dependence, off-target profiling, and toxicity/function rescue in patient iPSC-neurons or relevant models. Closure requires sequence or structural design principles that achieve therapeutic mutant allele suppression while preserving sufficient wild-type expression.
Evidence summary
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