Spinocerebellar Ataxia (SCA)
Spinocerebellar ataxias (SCAs) constitute a group of dominantly inherited neurodegenerative disorders affecting the cerebellum and spinal cord. Our company is committed to driving progress in therapeutic and diagnostic innovations within the SCA field through ongoing research, innovation, and collaborations with industry leaders.
Introduction to SCA
Spinocerebellar ataxia (SCA) is a rare disease with a global prevalence of approximately 3/100,000, but there are large regional variations. These conditions typically manifest in mid-life, characterized by initial ataxic symptoms such as gait, speech, and eye movement incoordination, followed by a range of non-ataxic symptoms including cognitive deficits, cranial nerve dysfunction, spasticity, and dystonia.
Pathogenesis of SCA
Forty-eight SCAs have been identified thus far, with each SCA designated by a number following the prefix SCA, reflecting the sequential order of the discovery of the genetic mutation. The most prevalent SCAs, such as SCA 1, 2, 3, 6, 7, 17, and DRPLA, are caused by the expansion of CAG trinucleotide repeats encoding polyglutamine tracts in protein products. These polyglutamine SCAs, accounting for over half of known SCAs, stand as the most well-characterized in terms of genetic mechanisms.
In addition to polyglutamine repeat expansions, pathogenesis in other SCAs such as SCA 8, 10, 12, 31, 36, and 37 involves nucleotide repeats occurring outside of coding regions, potentially resulting in toxic RNA species or aberrant peptide products through non-canonical translation processes such as repeat-associated non-ATG initiated translation (RAN translation).
Fig.1 Ataxin-1 modulating therapies. (Kerkhof, Laurie MC, et al., 2023)Animal Models of SCA
The development of therapeutic approaches for SCA necessitates accurate disease models for research and drug testing. Various animal models have been employed, including mouse, fly, and zebrafish models.
- Mouse Models: The B05 transgenic mouse model expresses the human ATXN1 gene with 82 CAG repeats under the Pcp2 promoter, resulting in cerebellar Purkinje cell dysfunction and ataxic phenotypes. Another key model, the SCA1154Q/2Q knock-in mouse, mirrors motor deficits, muscle wasting, and cognitive impairments observed in SCA1.
- Insect Models: The Drosophila melanogaster fly model has provided insights into SCA1 pathology. The fly model expressing human 82Q ATXN1 exhibits nuclear inclusion formation and neurodegeneration.
Therapeutics Development of SCA
Targets of SCA Therapy Development
Regarding symptomatic therapy, a promising avenue involves the modulation of ion channels implicated in cerebellar circuitry dysfunction associated with ataxia. Potassium channels, particularly small-conductance, calcium-activated channels, present attractive targets for therapy. Compounds like chlorzoxazone, NS13001, and riluzole have shown promise in improving ataxia symptoms in preclinical and clinical studies, emphasizing the importance of targeting ion channels in SCA therapy development.
Types of SCA Therapy Development
Disease-modifying therapies for SCA are actively being pursued, with a focus on reducing toxic mutant protein levels. Strategies involving RNA depletion and DNA editing are emerging as promising avenues. Furthermore, gene-editing technologies like CRISPR/Cas9 show potential in treating SCA by correcting the genetic abnormalities underlying the disorder.
Our Services
Our company offers cutting-edge diagnostic development services for SCA. Leveraging advanced techniques such as whole-genome sequencing and whole-exome sequencing, we ensure comprehensive screening for known SCA genes and potentially novel genetic causes of SCA. Our expertise extends to the detection and characterization of repeat-expansion mutations crucial for diagnosing and stratifying SCAs.
Platforms of SCA Therapy Development
Animal Models of SCA
- B05 transgenic models
- SCA154Q/2Q knock-in models
- Others
Our company is committed to advancing knowledge in the field of neurogenetics and contributing to the development of innovative therapeutics for SCA. If you are interested in our services or require further information, please contact us, and our team will be happy to assist you.
Reference
- Kerkhof, Laurie MC, et al. "Therapeutic Strategies for Spinocerebellar Ataxia Type 1." Biomolecules 13.5 (2023): 788.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.