Approaching the age of clinical therapy for spinocerebellar ataxia type 1

Written by Dr. Marija Cvetanovic Edited by Dr. Maxime W. Rousseaux

New research (published Nov. 2018) reveals promising potential genetic therapy for SCA1.

A research team comprised of scientists from academia and industry have tested a new treatment for Spinocerebellar ataxia type 1 (SCA1), bringing disease-modifying therapy one step closer to the clinic. SCA1 is a dominantly-inherited ataxia that is currently untreatable. Symptoms of the disease include progressive loss of balance, slurring of speech, difficulties with swallowing and coughing, mild cognitive impairments, and depression. With a life expectancy after diagnosis of only 10-15 years, SCA1 is one of the fastest-progressing SCAs: after symptoms first appear, patients typically have just over a decade before these symptoms become so severe that they cause death (often due to respiratory failure). In 1993, collaborative efforts from the laboratories of Drs. Harry T. Orr and Huda Y. Zoghbi discovered that SCA1 is caused by the expansion of a CAG repeat somewhere in a patient’s DNA. CAG repeats cause a polyglutamine expansion in the protein that the mutated gene encodes; in this case, the group later identified that this had occurred in Ataxin-1 (ATXN1), the gene that encodes the ATXN1 protein. The SCA1 mouse models that Drs. Orr and Zoghbi generated (and graciously shared with the scientific community) have allowed for significant advances in the understanding of SCA1 pathogenesis over the years. Now, they provide preclinical evidence of a promising therapy to alter the progressive motor deficits and fatal outcome of SCA1.

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This therapeutic approach makes use of antisense oligonucleotides (ASOs) to reduce levels of toxic ATXN1 protein. ASOs are short oligonucleotides that can reduce, restore, or modify protein expression through several distinct mechanisms. Over the years many advances in the understanding of ASO pharmacology have improved their stability, delivery, specificity and safety, thus providing momentum for their use in the clinic. ASO approaches have already been used to improve disease symptoms in preclinical animal models of several neurodegenerative diseases, including SCA2, SCA3, and spinal muscular atrophy (SMA).

Previous research has provided support for any therapeutic approach that reduces expression of mutant ATXN1. Specifically, reducing the expression of mutant ATXN1 (especially during the early stages of disease) improves motor performance in mouse models of SCA1. Other studies have used ATXN1 RNA interference via virus injections, which proved to be an effective way to reduce ATXN1 expression and alleviate SCA1-like symptoms in mice. These particular results make ASO treatment all the more promising, since RNA interference is the main mechanism of action for ASOs.

The investigators tested the therapeutic potential of ASOs targeting mouse Atxn1 in their mouse model of SCA1 (a genetically-engineered line known as “Atxn1154Q/2Q knock-in mice”). ASOs were delivered at an early stage of disease by a single injection into the lateral ventricles of these mice’s brains. This led to a decreased expression of Atxn1 throughout the brain and rescued motor impairments (measured with rotarod and balance beam tests, which require fine motor skills like coordination and balance). Perhaps most importantly, ASO-injected mice lived more than 20% longer, indicating that this therapeutic approach might be able to help alleviate the premature lethality we see in human SCA1. Gene expression analysis and biochemical testing of the cerebella and brainstem – brain regions whose degeneration are thought to cause motor deficits and premature lethality in SCA1 – confirmed the reversal of SCA1 abnormalities.

This study is important because it supports the efficacy and therapeutic benefits of targeting ATXN1 expression with ASOs as a strategy for treating both motor deficits and lethality in SCA1. Additionally, by targeting the source of the pathogenesis (the formation of toxic ATXN1 protein), ASO-mediated therapy has a higher chance of success than therapies targeting downstream pathways. Together with advances in non-invasive techniques to objectively monitor disease progression, including magnetic resonance imaging (MRI) and magnetic resinance spectroscopy (MRS), this study heralds the age of SCA1 clinical trials and hope for successful therapy.

Finally, this study is a lasting legacy of Jillian Friedrich, a bright leading investigator in this study and a wonderful and beloved colleague, who passed away last year due to injuries from a biking accident.

Key Terms

ASOs (antisense oligonucleotides): short, synthetic oligodeoxynucleotides that can alter RNA and reduce, restore, or modify protein expression.

Polyglutamine expansion disorder: in about 60 of our genes, there is a DNA code that instructs cells to make small molecular machines (known as proteins) that have large, repeating chemical structures. These structures are made up of the chemical glutamine. While glutamine repeats serve a valuable function under normal conditions, they can also be quite unstable. In polyglutamine expansion disorders, the process of copying these repeating DNA codes becomes disrupted sometime early in development, causing an out-of-control expansion of the number of glutamines that a protein is supposed to contain. Because each gene has a different function, the gene in which a polyglutamine expansion occurs determines which disease a patient has – for example, SCA1 occurs from a polyglutamine expansion in the ATXN1 gene, while Huntington’s disease occurs from a polyglutamine expansion in the IT15 gene.

Conflict of Interest Statement

M. Cvetanovic declares no conflicts of interest. M. Rousseaux was previously a postdoctoral fellow in Dr. H Zoghbi’s laboratory and published papers with Dr. H. Orr. He was not involved in the current study.

Citation of Article Reviewed

Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles.  Friedrich J, Kordasiewicz HB, O’Callaghan B, Handler HP, Wagener C, Duvick L, Swayze EE, Rainwater O, Hofstra B, Benneyworth M, Nichols-Meade T, Yang P, Chen Z, Ortiz JP, Clark HB, Öz G, Larson S, Zoghbi HY, Henzler C, Orr HT. JCI Insight. 2018 Nov 2;3(21). pii: 123193. doi: 10.1172/jci.insight.123193. [Epub ahead of print]  PMID: 30385727