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.

stethoscope on top of laptop
Photo by Pixabay on Pexels.com

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A novel therapeutic approach for the treatment of SCA3

Written by Larissa Nitschke Edited by Dr. Gülin Öz

Researchers in the Netherlands uncover a new way to treat SCA3

Upon receiving a conclusive diagnosis of Spinocerebellar Ataxia (SCA), hundreds of questions can appear in a patient’s mind: What is Spinocerebellar Ataxia? Why am I affected? How will my symptoms progress? What is the ultimate prognosis? Thankfully, years of research have enabled us to answer many of these questions for patients affected by Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease. Still, the most important question a patient could ask – How can I be healthy again? – has remained unanswered.

SCA3 is the most common form of Spinocerebellar Ataxia worldwide. It is passed down from generation to generation in affected families. Initial symptoms typically appear around midlife, but cases of much earlier and much later onset have been reported. At first, problems with movement coordination are the most noticeable, leading to an increase in stumbles and falls. At later stages, speech difficulties, muscle stiffness, and sleeping problems appear, leaving the patient fatigued during the day. The symptoms worsen over the course of 10 to 20 years, at which point affected individuals typically succumb to the disease. As with other SCAs, current options for SCA3 treatment are mainly limited to symptom management rather than treating the direct cause of the disease.

Artist's representation of DNA
Artist’s representation of DNA. Photo from Pixabay.

The genetic cause of SCA3 is the presence of excess copies of the DNA building blocks cytosine (C), adenine (A), and guanine (G) in the Ataxin-3 gene (Atxn3). Scientists refer to this type of mutation as an expansion of a triplet repeat, since the C, A, and G copies appear as sets of back-to-back CAGs. Because the CAG triplet is responsible for coding the amino acid glutamine (Gln or Q) in the Ataxin-3 protein, the repeat expansion results in an elongated glutamine (polyQ) tract. This faulty protein accumulates in cells and causes toxicity in specific regions of the brain. Since the 1994 discovery that SCA3 is caused by a polyQ expansion in Atxn3, scientists and physicians all over the world have been humbled by the question of how to help patients affected with SCA3. One specific angle of research has focused on the removal of the toxic protein altogether. However, one downside of this approach is that it would also cause the loss of normal Atxn3 function in patients. Atxn3 is critical for the degradation of unwanted proteins, which is necessary for the healthy functioning of all our body’s cells. It normally binds to little marks on proteins called ubiquitin chains (which tag proteins for removal), then cleaves these chains to facilitate the entry of proteins into the cell’s destruction machinery. Since treatment will need to be sustained over the span of a patient’s lifetime, the complete removal of Atxn3 might be harmful.

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ASOs clear toxic protein from cells, reducing ataxia in SCA2 mice

Written by Anna Cook and Dr. Alanna Watt Edited by Dr. Vitaliy V. Bondar

Scientists uncover a promising therapeutic avenue to treat spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) is a progressive ataxia caused by a mutation in the ATXN2 gene. This mutation causes a tract of the amino acid glutamine in the ataxin 2 protein to expand, making it toxic to cells. This type of mutation – known as a polyglutamine expansion – is common to several neurodegenerative diseases, including Huntington’s Disease and several forms of ataxia. One treatment strategy that has been devised for polyglutamine diseases such as SCA2 is to remove the toxic protein from cells. And, in their tour de force SCA2 paper from 20171, this is precisely what Scoles and colleagues attempted to do. Removing protein levels is a particularly promising strategy for SCA2, since previous research from the authors of this paper has shown that a complete loss of healthy ataxin 2 protein in cells does not cause any major detectable behavioural consequences in mice2.

Removing a toxic protein from a cell is not a simple task; in fact, it has only been done a handful of times in models of neurodegeneration. One way to eliminate a protein in neurons is to cause the RNA that encodes it to be degraded before it can make the protein. Through a collaboration with a company that specializes in this approach — Ionis Pharmaceuticals — the authors created their own short RNA molecules that matched the sequence and therefore bound to regions in the specific RNA that encodes the protein ataxin 2. These small molecules are known as anti-sense oligonucleotides (ASOs), and once they bind to their partner, they recruit the cell’s waste system to degrade the RNA. Currently, ASO therapy is one of the most promising methods researchers have developed to eliminate toxic proteins for a wide range of degenerative diseases.

blue stethoscope next to laptop computer
Image of stethoscope next to a computer. Photo by Negative Space on Pexels.com

After designing many of these molecules, the authors screened 152 different ASOs to determine which were most effective at lowering levels of the toxic protein. ASOs were applied to skin cells that had been donated by SCA2 patients, and levels of mutated ataxin 2 protein were measured. By picking out the designs that caused the greatest decrease in ataxin 2 levels, the authors narrowed down the original group of potential ASOs to give a shortlist of promising candidates. The authors then chose one ASO (ASO7) to test in mouse models of SCA2.

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Decreasing ATXN3 levels can alleviate some symptoms in an SCA3 mouse model

Written by Dr. Terri M Driessen  Edited by Dr. W.M.C. van Roon-Mom

Antisense oligonucleotides: a potential treatment for SCA3 that partially rescues SCA3 disease mouse models

Identifying new ways to slow down or delay neurodegenerative diseases has been a key research focus in the SCA field. There are many avenues that scientists can take to address this question. One method is to target the disease-causing protein: by lowering the levels of the disease-causing protein, scientists may be able to alter disease progression. These methods have recently been used in studies in other neurodegenerative disorders, like SCA2, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease.

Prior work by the laboratory of Hank Paulson at the University of Michigan has suggested these methods may also work in SCA3. They used antisense oligonucleotides (ASOs) to lower the SCA3 disease-causing protein. ASOs are short DNA sequences that bind to specific pieces of RNA. When the ASOs bind to RNA, it is broken down and no protein is made. The Paulson laboratory designed ASOs that bind to ATXN3, which is the RNA associated with SCA3. These ASOs were able to lower the expression of mutant ATXN3 (Moore, et al. 2017). Importantly, they were capable of lowering the expression of mutant ATXN3 in both mouse models of SCA3 and SCA3 patient fibroblasts (Moore, et al. 2017). By removing the SCA3-causing protein from cells, they predicted that the cells would have a better chance at surviving.

This previous work was promising, but several questions remained. How long would one ASO treatment work? Would the ASO work even after the SCA3 mice started showing symptoms? Are there any obvious side effects, like increased inflammation, after ASO injection? And importantly, would lowering ATXN3 levels help with motor coordination problems in SCA3 mice?

white lab mouse being held by person wearing gloves
Image of a mouse in a laboratory environment. Photo by Pixabay on Pexels.com

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RNA-binding Protein Found to Play a Role in SCA2 Neurodegeneration

Written by Dr. Hayley McLoughlin Edited by Dr. Gülin Öz

Is Staufen1 a kink in the SCA2 toxicity chain that can be exploited?

When a cell is stressed, it can initiate a mechanism to protect messenger RNAs (mRNAs) from harmful conditions.  It does this by segregating the mRNAs, then packaging them up in droplets known as RNA stress granules. ATXN2, the protein that is mutated in SCA2, has previously been reported as a key component in the formation of these RNA stress granules (Nonhoff et al., 2007).  This observation has led researchers to take a closer look at stress granule components, especially in the context of SCA2 disease tissues.

close of of chain with metal links
Image of a metal chain. If a “weak link” is found in the chain of events that go amiss in SCA2, scientists could focus on this area to research possible treatment.  Photo by Pixabay on Pexels.com

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