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VO659 is an allele-preferential antisense oligonucleotide product candidate being developed for patients with polyglutamine diseases including, Spinocerebellar Ataxia types 3 and 1 (SCA3, SCA1) and Huntington’s disease (HD). These polyglutamine diseases are caused by a CAG repeat expansion that results in an elongated polyglutamine tract that makes the resulting mutant protein toxic to nerve cells.
VO659 preferentially targets expanded CAG repeats in the mutant mRNA transcript and inhibits mRNA translation leading to reduction of mutant protein with the goal of stopping or reversing disease progression. In preclinical studies, significant reductions in mutant ATXN3 and ATXN1 protein levels were observed in SCA3 and SCA1 mouse models, respectively.
Additionally, significant reductions in mutant HTT (mHTT) protein and improvements in motor function were observed in R6/2 and Q175 HD mouse models. Allele preferential reductions of mHTT were also observed in HD patient fibroblasts.
Spinocerebellar ataxia (SCA) are a group of rare, progressive hereditary genetic disorders that affects the cerebellum, brain stem and spinal cord. More than 30 types of SCAs have been identified to date (SCA1–SCA36), and the most common SCAs (types 1, 2, 3, 6 and 7) are caused by translated CAG trinucleotide repeat expansions that encode elongated polyglutamine (polyQ) stretches in the respective disease proteins. Presence of the elongated polyQ stretch confers pathogenic properties to the resulting protein through a dominant gain-of-function mechanism, resulting in degeneration of specific neuronal subpopulations that differ between the different SCA types. For SCA1 and SCA3 disease manifestation includes ataxia of gait, stance, and limbs, dysarthria, and oculomotor abnormalities. To date, there are no disease-modifying therapies.
VICO’s lead antisense oligonucleotide product is designed to suppress these mutant proteins and slow or halt disease progression.
Huntington’s disease (HD) is a rare hereditary neurodegenerative disorder with a progressive and fatal course characterized by movement disorders, cognitive impairment, dementia and psychiatric manifestations including depression and psychosis. The disease has a wide variation in onset age, with an average age at onset of mid adulthood. Prevalence is an estimated 4-10 per 100,000 population. Today there is still a significant unmet need in disease-modifying therapies for the treatment and management of HD, with drugs that can alleviate some of the movement and psychiatric symptoms, but no curative treatments available.
The underlying genetic defect is a mutation in the gene encoding the global transcriptional regulator, Methyl CpG Binding Protein 2 (MECP2), located on the X chromosome. MECP2 is a global transcriptional regulator and essential for normal nerve development and function and acts as one of the many biochemical switches that can either increase gene expression or direct other genes when to turn off and stop producing their own unique proteins. VICO's therapeutic strategy is based on antisense oligonucleotide-mediated RNA editing to repair mutant MECP2 and reverse symptoms.