Designing a new “measuring stick” for ARSACS

Written by Dr. Brenda Toscano Márquez  Edited by Dr. Ray Truant

ARSACS researchers develop a better “measuring stick”, or disease severity index that can help better assess the progression of motor symptoms and compare different groups of ARSACS patients.

How does your doctor know you are sick? In short: measurements. Doctors record your weight, blood pressure, temperature, glucose levels, etc. The complex relationship between these biomarkers should indicate if you are healthy, or if not, to what degree you deviate from the healthy range.

Of course, each disease has a unique set of symptoms and characteristics. Performing the right measurements, with the right scales, is key to determining the type of disease, the course of treatment and most importantly, to know if the treatment is working. It would be careless and even dangerous if, for example, your doctor weighed you with a scale that could only detect a change of 10 kilograms. Even worse would be to focus on this measurement when you are actually suffering from high blood pressure.

yellow measuring tape wrapped up in ball
Photo by Marta Longas on

Patients with cerebellar ataxia also need physicians to perform the right measurements that take into account their particular type of ataxia. Proper measurements show how fast symptoms are progressing and if treatments and therapies are having an effect. Cynthia Gagnon and colleagues published a paper in the journal of Neurology this past year in which she and her collaborators designed a new set of measurements or “disease severity index” to track the symptoms better. The new index is designed for adult patients with a type of cerebellar ataxia called ARSACS. The researchers hope that this new index which they call DSI-ARSACS will help clinicians better assess how the disease is progressing, and will provide the means to compare different groups of patients.

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Snapshot: What is drug repurposing?

To repurpose drugs is to find new ways that they can be applied to treat other conditions and illnesses. Although our knowledge of diseases is greater than ever before, the development of novel therapies has yet to catch up. Drug development is slow, expensive and risky. These challenges have made drug repurposing a more attractive option in recent years. Drug repurposing can be quicker, more cost-effective, and less risky than traditional drug development strategies since the bulk of the work is already done. There are many ways to find new uses for old drugs. The process starts with finding evidence that a drug has useful effects, or new targets, outside of its current clinical use. Then the new mechanism is studied and tested. The process ends within traditional drug development, in some cases skipping the already completed safety phases, and instead focuses on how well the drug works for its new purpose.

pink medication tablets in a bubble packet
Photo by Pixabay on

The barriers to drug repurposing

Despite clear advantages of drug repurposing, there are numerous challenges to this process. The pharmaceutical industry and scientific community tend to focus on new and innovative therapies. While new drugs are certainly needed, an unintended consequence is overlooking many valuable drugs that already exist. Unfortunately, drug repurposing is not as lucrative as new drug development which particularly hurts rare disorders like SCA. With old drugs, patent protection and legal hurdles are also barriers hindering alternative use. And while drug repurposing is financially less risky, there always exists the possibility that a drug will fail somewhere in development. Finally, it is also important to keep in mind that not all drugs can be repurposed. Even if two disorders are similar, this does not mean that similar drugs can be used to treat them both.

Drug repurposing in practice

It is noteworthy that in addition to old drugs, drugs that have previously failed in treating one condition can be considered when developing treatments for other disorders. A notable example is the drug thalidomide, which infamously led to birth defects but has now been repurposed to treat certain blood cancers (Singhal et al., 1999) and leprosy (Teo et al., 2002). There are also several notable recent examples of drug repurposing in SCA. One example is the proposed repurposing of the drug 4-aminopyridine, or 4-AP. This drug, which is also used to treat multiple sclerosis, has been shown to aid with motor symptoms in a mouse model of SCA6. Hopefully, we will see more drugs repurposed to treat SCA and other rare disorders in the near future.

If you would like to learn more about drug repurposing, take a look at our past SCAsource article on drug repurposing in SCA6 or this resource by Findacure.

Snapshot written by Carlos Barba and edited by Dr. David Bushart.

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A novel gene therapy-based approach with therapeutic potential in SCA3

Written by Dr. Ramya Lakshminarayan Edited by Dr. Judit M. Perez Ortiz

Cholesterol to the rescue: An alternative approach to treating SCA type 3 using gene therapy.

Spinocerebellar ataxia type 3 (SCA3) is a movement disorder that is caused by genetic mutations in a protein named Ataxin-3. Neurons in the cerebellum, striatum, and substantia nigra are important for movement, and these are affected in SCA3.

The mutant form of Ataxin-3 builds up in these neurons, eventually causing neurodegeneration and neuronal loss. The abnormal accumulation of mutant Ataxin-3 is in part due to impaired protein clearance, which is a hallmark of many other neurodegenerative diseases. Degradation (breaking down) and clearance (getting rid of) of protein aggregates are therefore crucial in the pathophysiology of neurodegeneration.

The balance between protein synthesis (creation) and degradation (destruction) is critical to the health of neurons. One of the ways in which neurons degrade proteins is called autophagy. This process is mediated by organelles called lysosomes in cells. Lysosomes employ digestive proteins to break down complex protein aggregates into simpler forms, which are eventually recycled. Hence, the transport of proteins to lysosomes is an important step in protein degradation. In a recent study, Clevio and colleagues explore the role of cholesterol in mediating protein degradation and ensuring neuroprotection in SCA3.

laboratory scientisy using a pipette to transfer liquid between tubes
Photo of a researcher preparing samples, courtesy of Pixabay.

Cholesterol is a well-known biological molecule that is essential to cells for regulating various processes. However, abnormally elevated levels of cholesterol are associated with heart disease, and its production is the target of pharmacological therapies. As with proteins, homeostatic fine-tuning of cholesterol levels is maintained by a balance of production and degradation.  In many neurodegenerative disorders, such as Alzheimer’s disease and Huntington’s disease, cholesterol metabolism and turnover is impaired.  The cholesterol biosynthetic pathway facilitates production and its metabolism is mediated by an enzyme called cholesterol 24-hydroxylase (CYP46A1). CYP46A1 converts cholesterol to 24-hydroxycholesterol, a form capable of crossing the blood-brain barrier. This conversion allows the efflux of cholesterol from neurons. CYP46A1 is, therefore, necessary for cholesterol efflux and the efflux of cholesterol activates the cholesterol biosynthetic pathway. The cholesterol biosynthetic pathway produces many precursors important for protein transport and autophagy.

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Snapshot: The next-generation of CRISPR is prime editing – what you need to know

The CRISPR gene-editing toolbox expanded with the addition of prime editing. Prime editing has astounding potential for both basic biology research and for treating genetic diseases by theoretically correcting ~89% of known disease-causing mutations.

What is prime editing?

Prime editing is coined as a “search-and-replace” editing technique that builds on the “search-and-cut” CRISPR technology. Like CRISPR, prime editing utilizes the Cas9 enzyme targeted to a specific location in the genome by a guide RNA (gRNA). With a few ingenious modifications, including an enzyme called a reverse transcriptase (RT) fused to Cas9, prime editors can be targeted to nearly anywhere in the genome where the RT writes in new DNA letters provided by a template on the gRNA.

graphic drawing of red handled scissors
New gene-editing techniques offer more opportunities for therapy development. Each new discovery makes the techniques more and more accurate. Image courtesy of yourgenome.

 How is prime editing different from CRISPR?

Scientists are excited about prime editing because it has several advantages and overcomes many of the limitations of previous CRISPR systems. CRISPR Cas9, an endonuclease, cuts—like scissors—both DNA strands to inactivate a gene or to insert a new sequence of donor DNA. Unlike CRISPR edits, the prime editing Cas9, a nickase, cuts a single DNA strand and does not rely on the cell’s error-prone repair machinery, thereby minimizing any resulting deleterious scars left on the DNA. It has a broader range of targets because it is not limited by the location of short DNA sequences required for Cas9 binding to DNA. The versatility and flexibility of the system allows for more control to inactivate genes as well as to insert, remove, and change DNA letters, and, combine different edits simultaneously—analogous to a typewriter. Importantly, the edits are precise with relatively infrequent unwanted edits. Initial indications showed fewer off-target edits in the genome, possibly because more steps are required for a successful edit to occur. In some cases, it may be more efficient than CRISPR, depending on the targeted cell type, such as in a non-dividing cell like a neuron in the brain. However, with all these advantages, CRISPR still remains the tool of choice for making large DNA deletions and insertions because the prime editing system is limited by the RT and template RNA length.

How could prime editing help ataxia patients?

Prime editing offers enormous possibility for correcting heritable ataxia mutations accurately and safely. In dominantly inherited SCAs, like SCA1 or SCA2, prime editing could shorten the pathogenic repeat expansion allele to the normal length, or inactivate the pathogenic allele without creating unwanted, deleterious mutations. It also provides researchers with a powerful tool to study disease-causing genes in cells and animal models in new ways to advance our knowledge about the underlying mechanisms in ataxia.

What barriers are there to using prime editing as a treatment?

Prime editing will require rigorous testing in cells and animals before moving into humans in a clinical trial. Optimizing delivery and efficiency in target cells and tissues, and minimizing side-effects will be the key barriers to overcome.

To read the original Nature article describing prime editing, it can be found from the Liu lab here.

If you would like to learn more about Prime Editing, take a look at these news stories by The Broad Institute and Singularity Hub.

Snapshot written by Bryan Simpson and edited by Dr. Hayley McLoughlin.

How an ataxia gene increases the risk for Alzheimer’s disease

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.

artist's sketch of a human brain, designed to look like electrical circuits
Drawing of a human brain, courtesy of Wikimedia.

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.

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