Written by Dr. Judit M. Perez Ortiz Edited by Dr. Marija Cvetanovic
In a tour de force study, a collaborative team of scientists led by Dr. Rudolph Tanzi (Harvard Medical School) and Dr. Huda Zhogbi (Baylor College of Medicine) found a novel relationship between the Spinocerebellar ataxia type 1 gene (ATXN1) and Alzheimer’s disease.
Alzheimer’s disease is the most common neurodegenerative disease and the most common cause of dementia. Its precise etiology remains the subject of intense investigation and debate. Alzheimer’s is a devastating disease. Persons with Alzheimer’s disease experience difficulties thinking and remembering things. As the disease worsens other symptoms begin to appear, such as getting lost easily, not recognizing loved ones, problems with language, and behavioral and psychiatric issues. In the more advanced stages, patients are completely dependent on their caregivers.
Despite extensive research, a specific unifying cause of Alzheimer’s disease has not yet been identified, likely due to its complexity. There are a handful of genes responsible for a rare form of early onset Alzheimer’s disease that affects younger patients. However, the great majority of cases start late in life and have no known underlying cause (termed sporadic). While the major risk to develop Alzheimer’s disease is advanced age, scientists believe that clues to sporadic Alzheimer’s can be found in our genes. In this pursuit, hundreds of “risk genes” have been associated with Alzheimer’s disease and Ataxin-1 (ATXN1) has recently emerged as one of such risk genes. Yet how ATXN1 influence Alzheimer’s disease was not understood.
The instructions our bodies need to grow and function are contained in our genes. These instructions are made up of tiny structures called nucleobases. There are four types of nucleobases in DNA: adenine (A), cytosine (C), guanine (G), thymine (T). By putting these four nucleobases in different orders and patterns, this writes the instructions for our body.
Some of the genes contain long sections of repeating ‘CAG” instructions, called CAG tracts. Everyone has repeating CAG tracts in these genes, but once they are over a certain length they can lead to disease. Some ataxias are caused by this type of mutation, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. These are often called polyglutamine expansion disorders. This is because “CAG” gives the body instructions to make the amino acid glutamine. You can read more about what is polyglutamine expansion in our past Snapshot about that subject.
For each disorder caused by a CAG expansion mutation, the number of times the CAG is repeated in a particular gene will determine whether someone will develop the disease. Repeat lengths under this number will not cause symptoms and repeat lengths over the threshold will usually lead to ataxia. When someone undergoes genetic testing for ataxia, doctors will be able to tell them the length of these CAG tracts and whether they have a CAG repeat number in one of these genes that is over the threshold. This table gives a summary of different CAG expansion mutations that can lead to ataxia and how the length of the repeat affects age of onset.
Normal Repeat Size
Disease Repeat Size
For SCA1, SCA2, SCA3, SCA6, and SCA7; longer CAG tracts are associated with earlier onset.
For SCA12, it is hard to predict the age of onset based on repeat length as SCA12 is so rare. Some individuals with long repeats don’t develop ataxia. One study found that longer CAG tract lengths are associated with earlier onset but that it does not affect the severity of symptoms.
For SCA17, Longer CAG tracts have separately been associated with an earlier age of onset and more severe cerebellar atrophy.
In general, people with longer repeat lengths in ataxia genes are likely to present with ataxia symptoms earlier in life. However, it is important to remember that there are many other factors involved. Other genes may have mutations that either worsen the progression of ataxia or protect against more severe symptoms. Therefore, in individual people, the length of the repeat is not always enough information to determine when that person will start showing symptoms, or how severe these symptoms will be.
If you would like more information about the genetic causes of SCAs, including information about genetic testing and what CAG repeat length might mean, take a look at these resources by the National Ataxia Foundation.
Snapshot written by Anna Cook and edited by Larissa Nitschke.
Written by Dr. David Bushart Edited by Dr. Hayley McLoughlin
A newly-proposed treatment strategy might be effective against several forms of spinocerebellar ataxia and other CAG repeat-associated disorders
Upon receiving an initial diagnosis of spinocerebellar ataxia (SCA), a swarm of questions might enter a patient’s mind. Many of these questions will likely revolve around how to manage and treat their disease. What treatments are currently available to treat SCA? What can I do to reduce symptoms? Does SCA have a cure, and if not, are researchers close to finding one? Patients and family members who read SCASource may be able to answer some of these questions. Although scientists are aware of some of the underlying genetic causes of SCA, and patients can benefit greatly from exercise and physical therapy, there are unfortunately no current drug therapies that can effectively treat these diseases. However, this is a very exciting time in SCA research, since researchers are hard at work developing new treatment strategies for several of the most common SCAs. Many of these newly proposed therapies are specialized to treat a specific genetic subtype of SCA (e.g. SCA1, SCA3, etc.), which would allow these therapies to be very specific. However, these specialized efforts beg another question: would it be possible to treat different types of SCA with the same therapeutic strategy?
This is precisely what researchers wished to determine in a recent study, authored by Eleni Kourkouta and colleagues. This group of researchers used a technology called antisense oligonucleotides (often abbreviated ASO, or AON), to ask whether a single ASO could be used to treat multiple neurological disorders that have different underlying causes. Currently, most ASO technology depends on our ability to selectively target specific disease-causing genes, which allows the ASO to only recognize and act on the specific gene that is causing ataxia. Once recognized, these ASOs can recruit cellular machinery that lowers RNA levels of the disease-causing gene, thereby greatly limiting the amount of disease-causing protein that is produced (learn more in our What is RNA? Snapshot). This strategy has the potential to be very effective for treating SCAs that are associated with polyglutamine (polyQ) expansion (learn more in our What is Gene Therapy? Snapshot).
However, the type of ASO technology described above is not the only way to reduce levels of the disease-causing proteins in SCA. In this paper, Kourkouta and colleagues use a different type of ASO with a different mechanism of action, which also lowers levels of the disease-causing protein in two different SCAs.
Written by Dr. Sriram Jayabal Edited by Dr. David Bushart
Eye movement deficits occur ubiquitously in spinocerebellar ataxias, even at early disease states, highlighting their clinical importance.
Imagine the different motor movements that you make in your everyday life. Many people think of actions that we perform using our hands and legs, such as reaching for objects or walking. Let’s zoom in on a different task: catching a baseball. You need to know where the ball is going to land so you can run to that spot, then guide your arms while diving, if need be, to catch the ball. For this to work perfectly, you need to see and follow the ball. Your eyes enable you to track the ball while it is moving. How can your eyes keep the ball in focus while you are running at full speed towards the spot where you expect the ball to land? Your eyes are equipped with muscles which enable the eyes to move so as to keep the visual scene in focus. These eye movements, as demanded by the needs of the current scenario, in this case, catching a baseball, are indispensable for us to see the world without any hindrance.
Which brain region gives us the power to do this?
The cerebellum, or “little brain”, which enables one to move their arms and legs precisely, also controls the way we move our eyes. Therefore, it is logical to posit that when cerebellum goes awry, it may lead to eye movement abnormalities. Several previous studies have shown this to be true in many spinocerebellar ataxias (SCAs), where non-gait symptoms such as eye movement abnormalities have been found to accompany gait deficits in advanced stages of the disease. However, recent work from pioneers in clinical ataxia research at the Harvard Medical School have shown that eye movement abnormalities are also commonly present in SCAs even in pre-symptomatic states. This study emphasizes the critical need to better document the history of eye movement deficits and track them throughout the progression of the disease. This will help researchers to develop better rating scales for ataxia.
In this study, a population of SCA patients (134 individuals) who exhibited different types of SCA (including SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 and SCA17) were assessed for eye movement abnormalities at different stages of the disease, from pre-symptomatic (with no gait deficits) to advanced stages (those who use a wheel-chair). First, it was found that ~78% of all pre-symptomatic individuals exhibited eye movement deficits, and these deficits became even more common as the disease progressed, where every single person in advanced stages exhibited eye movement deficits. Second, when researchers examined the eye movements closely, they found that different types of ataxia might cause different kinds of eye movement deficits. However, these results are only suggestive because of the small population size of early-stage SCA individuals in this study, and the types of assessments used. Therefore, future studies will require a larger population size and a thorough quantitative analysis of specific types of eye movement deficits to help characterize eye movement abnormalities in SCAs. Finally, the Brief Ataxia Rating Scale (BARS), a recently designed simple clinical test for ataxia, was further improved in this study to account for the clinically observed eye movement deficits in SCAs. With such a nuanced metric, an improved BARS score was found to correlate with the stage, severity and duration of the disease irrespective of the type of ataxia.
Research is rapidly moving from the bench to the bedside to treat neurological inherited disorders of all types, including spinocerebellar ataxias. SCAsource has previously gone over the science behind ASO therapy. These diseases share a common theory that the DNA mutation leads to the formation of an altered protein that is toxic. ASO therapy is meant to stop the formation of the toxic protein by “shooting the messenger”.
What is involved in these clinical trials?
To see what might happen in ataxia trials, let’s look at ASO trials happening right now in related polyglutamine diseases. In Huntington’s disease (HD), there are two programs that are currently in clinical trials. Regulatory authorities view ASOs as drugs and require that the product be shown to be both safe and effective in patients.
ASOs cannot be given as pills and they are currently injected into the spinal fluid. This is called intrathecal administration to get the drug directly in the fluid space where it can circulate back to the brain. Patients in phase 1 studies in HD are asked to have up to 7 injections and one phase 3 program requires injections every second month for 2 years. This involves a large commitment to the study and is asking a lot from patients and their families.
The only published phase 1 double-blind, placebo-controlled study in HD (Tabrizi et al., New England Journal of Medicine, 2019) has identified that a series of 4 injections were safe. They measured changes of the “bad” protein in the spinal fluid as a proof of concept that ASOs could lower protein levels. The good news was that they found that there was a dose-related reduction in this protein of about 40%. Patients from this study were offered “open label” monthly injections and this has shown a 60% reduction in the abnormal protein according to a recent presentation. Open label extensions are when patients can continue taking a drug after the formal time of the clinical trial is over.
So, what does success mean?
The phase 3 studies that are currently ongoing in HD are designed to see if there is a slowing of disease progression. This is being measured by assessing motor, cognitive and behavioral symptom change over time. Changes occur slowly in HD and SCA. Therefore, large numbers of patients are required over a relatively long study time.
The bottom line is that a successful study that shows slowing disease progression is likely to mean that the patients may not experience any obvious improvement while receiving the treatment and that they will continue to have progressive symptoms over time. Hopefully, this will be at a slower rate compared to the placebo group. Since there are no treatments available for SCA or HD, this will be welcome. It is by no means considered to be a cure or likely to stop the progression. True cures in medicine are rare, where a cure is defined as a drug ending disease.
In the HD research community, we are asking questions that include:
Is it a good idea to reduce the good protein that is part of our normal brain chemistry? In the current phase 3 study, the ASO reduces both the “good” and the “bad” HD protein. Another program in phase 1 uses an ASO that only reduces the “bad” protein.
When is the best time to use ASO therapy? Since these conditions are associated with nerve cell damage and loss, it makes sense to use these types of therapy very early, even before damage occurs. This will mean that patients with moderate or advanced symptoms may not be good candidates for ASO therapy.
Should we consider treatment in people who have had predictive genetic testing before symptoms start? This is being actively discussed but it is too early to consider this. We have to show that ASOs are safe and effective in symptomatic patients. We need to have good measures to determine if treatments are working. Regulatory authorities have required evidence that treatments have a positive effect on patients lives. This may be difficult to show in a short study. We must consider that it takes patients decades to get these diseases: slowing or stopping this could take just as long.
We can only figure out the answers to these questions in clinical trials. The goals of these trials are to improve people’s quality of life. To do this we need information from real people with these diseases, and not just models of disease. This is a process that will take time but will tell us which approach has the most promise and is worth pursuing faster. Thus, the patients and families at this point are just as important as the researchers in lab coats working together to treat these diseases.
If you would like to learn more about clinical trials, take a look at this resource by the FDA or our previous Snapshot on the subject.
Snapshot written by Dr. Mark Guttman and edited by Dr. Ray Truant.