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
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Spinocerebellar Ataxia Type 1 is Caused by a Trinucleotide DNA Repeat

Written by Hillary Handler  Edited by Dr. David Bushart

How researchers found that SCA1 is caused by an expanded, repetitive DNA sequence – a discovery that has allowed for accurate SCA1 diagnosis and more focused research strategies

Before the true genetic basis of Spinocerebellar Ataxia Type 1 (SCA1) was discovered, researchers and medical doctors noticed that SCA1 causes motor dysfunction, death of specific types of brain cells, and premature death in affected patients. By assessing health outcomes in multiple families affected by SCA1, scientists also recognized that the disease is inherited in an autosomal dominant manner. This means that each person with an SCA1 diagnosis has a 50% chance of passing the disease to each of his or her children. In addition, researchers noticed that affected members of SCA1 families displayed a disease feature called anticipation: a trend of increasing symptom severity and earlier age-of-onset as the disease is passed from generation to generation. Despite these discoveries, the specific genetic mutation responsible for causing SCA1 had not yet been identified or described. Determining the genetic cause of an inherited disease is critical for allowing accurate diagnosis of the condition. Furthermore, understanding the genetics of SCA1 would provide researchers with important clues about disease pathology that could help with designing and developing treatments.

Researcher looking through a microscope
Photo by Pixabay on Pexels.com

 

One of the groups that sought to identify the specific genetic cause of SCA1 was led by Dr. Harry Orr. These researchers published their findings in a landmark 1993 paper (Nature Genetics, 1993), which described the process by which they made their discovery. First, a technique called “linkage analysis” was used to determine the general location of the SCA1 gene within the human genome. By tracking how SCA1 is inherited relative to other, well-characterized genetic locations, the team was able to narrow their search to a small portion of chromosome 6’s short arm known as region 6p22-6p23. The researchers also noted that anticipation is often indicative of a particular DNA feature known as a trinucleotide repeat. To determine if a trinucleotide repeat was indeed causing SCA1, these scientists used DNA cloning and screening techniques within the identified region of chromosome 6. These experiments identified a CAG trinucleotide repeat within the SCA1 genomic target region of DNA.

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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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DNA Damage Repair: A New SCA Disease Paradigm

Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin

Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms

The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.

dna-2358911_1280
Artist representation of a DNA molecule. Image courtesy of gagnonm1993 on Pixabay.

DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.

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