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RNA
Modalities in Huntington’s Disease Therapy
Reported by Jill
Crittenden.
Abstract:
Key deliberation at the workshop RNA
Modalities in Huntington’s Disease Therapy concerned how to tailor
therapeutic RNAs for the treatment of Huntington’s disease (HD). This meeting
was spurred by the recent discovery that small interfering RNAs (siRNAs) can be
used in mammals to degrade complementary messenger RNA. Discussions focused
primarily on the mechanism and design of siRNAs, but also touched on recent
progress in the therapeutic application of ribozymes and aptamers (RNAs that
cleave or that inhibit/activate target molecules, respectively). The choice
target for destruction by therapeutic RNAs was the huntingtin transcript,
although notable mention was given to other targets that might contribute to the
disease phenotype such as the aspartic protease and CREB binding protein (CBP).
For both target-specificity and overall safety it was deemed essential to
develop vectors in which the expression of RNA can be tuned to therapeutic
levels. Proposals for how to specifically disrupt the mutant huntingtin
transcript without destroying the function of the normal allele included 1)
targeting an siRNA to a single nucleotide polymorphism (snp) specific to the
disease transcript, 2) introducing a wildtype HD transgene that is resistant to
the therapeutic RNA and 3) designing a ribozyme that cleaves only transcripts
with an extended polyglutamine repeat. Several participants described their
success in using the first strategy to specifically disrupt disease transcripts,
thus underscoring the need to identify ample snps within the mutant HD gene to
test for use in siRNA-mediated degradation (not all siRNA sequences are
effective). It is not yet known whether introducing siRNAs directly into the
brain would be sufficient to confer long-term suppression, therefore, several
participants arranged collaborations to test this using reporter genes in rodent
models. The latter part of the workshop focused on a familiar topic: how best to
deliver therapeutic agents to the brain. Attending virologists gave promising
reports of how new methods combined with the latest generations of adenovirus,
adeno-associated virus and lentivirus are improving delivery in animal models.
The use of synthetic delivery systems may be further from clinical application.
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