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SKY-0515

Huntington's disease

Last updated
211 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Mechanism of action

4 evidence topics · 5 sources

HTT lowering through splicing modulation

“SKY-0515 is designed to reduce mHTT protein levels by lowering of HTT messenger RNA (mRNA) through a splicing mechanism, leading to a decrease in both wild-type and mutant forms of HTT protein.” (opens the source at this quote in a new tab)

“Additionally, the drug lowers postmeiotic segregation 1 (PMS1) protein, which plays a role in somatic CAG repeat expansion-a key driver of HD progression.” (opens the source at this quote in a new tab)

Molecular mechanism: cryptic exon inclusion in HTT pre-mRNA

“Inducing the 5’ss of intron 49b to include poison exon 49b introducing a premature termination codon and destabilizing HTT mRNA” (opens the source at this quote in a new tab)

Rationale for PMS1 lowering

“PMS1 contributes to somatic instability of the CAG repeat expansion, particularly in striatal neurons. Continued expansion of the repeats leads to increased cellular toxicity and is a key driver in time to disease onset and progression.” (opens the source at this quote in a new tab)

Target selectivity: independent commentary

“SKY-0515, like PTC Therapeutics’ votoplam, isn’t specific for huntingtin.” (opens the source at this quote in a new tab)

“we currently have no direct evidence that the reductions in PMS1 reported by SKY-0515 are actually slowing somatic expansion in the brains of people with HD” (opens the source at this quote in a new tab)