SCA3 Program Overview

Cure Rare Disease is currently developing a therapeutic to treat Spinocerebellar ataxia type 3 (SCA3), a rare, progressive neurodegenerative disease. In this blog, we will break down how this therapeutic works to combat disease progression.

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About Spinocerebellar Ataxia type 3 (SCA3)

Spinocerebellar ataxia type 3 (SCA3) is caused by mutations in the ATXN3 gene, which codes for the protein ataxin-3. Ataxin-3 is found in cells throughout the body and is involved in the process that removes damaged or extra proteins. It is believed that ataxin-3 is also involved in transcription, the first stage of protein synthesis. The disease is caused by a repetition in a part of the genetic code for the ataxin-3 protein. This increase in the number of CAG repeats in the ATXN3 gene, as shown in the graphic below, results in an ataxin-3 protein that is now toxic to the cells in the brain. The disease has a global prevalence of approximately 1 to 5 in 100,000 people. 

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Every person has 2 copies of the ATXN3 gene, one inherited from each parent. SCA3 has an autosomal dominant inheritance pattern. This means that for a person to have the disease, they only need to inherit 1 mutant copy of the gene from 1 parent. Symptom onset is variable and ranges from childhood to late adulthood. Symptoms include motor impairment, difficulty swallowing or speaking, impaired eye movement or vision, nerve damage, twitching in the face and tongue, muscle spasms, or abnormal posture due to abnormal muscle tone. People with SCA3 typically live between 6 and 20 years after onset of the disease. Choking and aspiration pneumonia are two of the more common causes of death in these patients.

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There are currently no approved therapeutics for SCA3 patients that can slow the progression of the disease. The standard of care includes physical therapy to delay loss of ambulation. At this time, medications can only be taken to manage symptoms.  

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What type of therapeutic is Cure Rare Disease developing to treat SCA3?

Cure Rare Disease is developing an antisense oligonucleotide (ASO) to treat SCA3. ASOs are single stranded molecules that are complementary to a specific sequence of messenger RNA that they are targeting. As a result, they are able to bind to one another like magnets. ASOs can have many different working mechanisms, including downregulation of a given messenger RNA and modification of a messenger RNA by splice switching. You can read more about how ASOs work here. 

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How does CRD’s ASO therapeutic work?

CRD is employing a splice-switching antisense oligonucleotide to reduce the toxicity of the ataxin-3 protein in SCA3 patients. The ASO targets exon 10 of the unprocessed, or pre-mRNA. This exon 10 contains the expanded CAG repeat. Through a process known as steric blocking, the ASO binds with the pre-mRNA such that the cellular machinery involved in processing does not recognize exon 10 and doesn’t include it in the final transcript. The resulting protein will be slightly shorter, does not contain the toxic mutation but still contains most of its essential functional domains. 

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Preclinical in vitro and in vivo experiments have demonstrated production of a functional ATXN3 protein and reduces disease phenotype in the brain. 

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Who is eligible to receive this treatment?

All SCA3 patients have an expansion of CAG repeats in the ATXN3 gene. This treatment is applicable to all SCA3 patients because it targets the ataxin-3 RNA.

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Who is Cure Rare Disease collaborating with to develop this therapeutic?

Cure Rare Disease is collaborating with the NeuroD lab of Willeke van Roon-Mom at Leiden University Medical Center in Leiden, Netherlands to develop this ASO therapeutic along with our CRO and CDMO partners. Our clinical partner for the program is Dr. Susan Perlman, a world renowned movement disorder clinician at UCLA.