Snapshot: What Does Success Mean in Clinical Trials with Antisense Oligonucleotides (ASO)?

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.

medical doctor in blue scrubs and a white lab coat holding a stethoscope. They are off to one side, so only have their body can be seen, not inclduing their face.
What will ataxia clinical trials involving ASOs look like in the future? What will success look like?

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.

Graphs of symptoms vs time. The "typical progression" line has more symptoms more quickly. The "delayed progression after potential treatment" line has fewer symptoms, but still increases over time.
Graph explaining how a potential ASO treatment might work in the future. Although it might not make symptoms go away completely, it could reduce how severe symptoms are, the number of symptoms, and/or delay when symptoms first appear. Illustration by Celeste Suart.

In the HD research community, we are asking questions that include:

  1. 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.
  2. 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.
  3. 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.

New Strategy for Reducing Ataxin-1 Levels Shows Promise

Written by Carrie A. Sheeler Edited by Dr. Ronald A.M. Buijsen

RNAi reduces levels of disease-causing Ataxin-1 in SCA1 model mice, easing symptoms of disease when injected both before and after symptom onset.

Lowering the amount of the disease-causing mutant Ataxin-1 protein in affected cells and tissues improves symptoms of disease in spinocerebellar ataxia type 1 (SCA1) mouse models. Like patients with SCA1, mouse models exhibit worsening coordination and degeneration of neurons, beginning in adulthood. Previous work has used genetic manipulation before disease onset (Zu et al 2004). This prevents or delays the onset of disease in SCA1 mouse models. When this is done soon after the onset of symptoms, associated markers of disease are reversed. This suggests that there is a window of time after symptoms start wherein mutant Ataxin-1 can be targeted to improve patient outlook. The 2016 paper by Keiser and colleagues seeks to further study this effect, using RNA interference as a strategy to reduce disease-causing levels of Ataxin-1. As there is no current treatment for Ataxin-1, this is an important step towards assessing possible treatment strategies that could be useful in patients.

female scientist holding a clipboard standing in a laboratory in fornt of a microscope. Books and pictures of neurons line the wall behind her
Cartoon of a scientist reading over results.

Current strategies seek to decrease the amount of Ataxin-1 made in cells by targeting messenger RNA (mRNA)- the blueprints for proteins in a cell- for destruction. RNA interference (RNAi) is one such method which harnesses normal cellular processes to degrade specific mRNAs. In Keiser’s 2016 paper, a modified virus carrying a short sequence of DNA is injected into the brain of a mouse with SCA1. When this virus is injected, the DNA sequence enters the cells of nearby brain regions and stops the production of specific mRNA. In this case, it is Ataxin-1 mRNA that is specifically targeted. As Ataxin-1 mRNA are destroyed, the amount of Ataxin-1 protein made in the cell decreases.

Continue reading “New Strategy for Reducing Ataxin-1 Levels Shows Promise”

Snapshot: What is recessive ataxia?

What is a recessive disorder?

A recessive disorder is one that has a specific disease mechanism. For a recessive disorder to occur, both copies of the causative gene must be mutated for a patient to show symptoms.  Ataxias that follow this disease mechanism are known as recessive ataxia. However, having a mutation in only one copy of the gene does not lead to a disorder. As people with only one mutated copy of the gene can pass on the defective gene, these people are known as an unaffected carrier. Recessive ataxias range in symptoms and severity but are linked by their disease mechanism. While none of the Spinocerebellar Ataxias (SCAs) are recessive, there are many types of recessive ataxias, including Autosomal Recessive Cerebellar Ataxia Type 1 and 2 (ARCA1 and ARCA2), Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), Friedreich’s Ataxia, and Ataxia Telangiectasia. For example, Friedreich’s Ataxia is caused by a trinucleotide repeat expansion in the frataxin (FXN) gene. People with only one expanded copy of the FXN gene do not show any symptoms, while people with two expanded copies of the FXN gene are affected by Friedreich’s Ataxia.

How are recessive ataxias inherited?

For every gene in our body, we have two copies, one that is inherited from our mother and one from our father. Both parents of an affected individual have to have at least one copy of the mutation for a child to be born with a recessive disorder. If both parents are unaffected carriers, each child will have a 1 in 4 chance of getting the disorder.

For a patient affected with a recessive ataxia, the chances of having a child affected by the same disorder are low. For a patient to pass on the disease, their spouse must have at least one mutated copy of the causative gene. In the case where a patient’s spouse is a carrier, children have an equal chance of being an unaffected carrier or being affected by the disease. However, carrier rates for ataxias are low in the population, which makes it unlikely that a patient’s spouse is also a carrier for the ataxia mutation.

Map showing the statistical chance of two unnafected carrier parents passing on a mutated gene (25% unaffected child, 50% carrier child, 25% affected child) or an affected parrent and unaffected carrier (50% carrier child, 50% affected child)
How recessive disorders are inherited. Image by Eder Xhako, created with BioRender

How can a patient prevent passing on a recessive disorder to their children?

Generally, when a patient with recessive ataxia passes on the disorder to their children, their spouse is an unaffected carrier. If you are a patient with a form of recessive ataxia and are thinking about having children, your spouse can undergo carrier testing to find out if they are a carrier for the same recessive ataxia. This will determine the likelihood that the recessive ataxia is passed on to your children. If it is determined that the spouse is a carrier, options like IVF with embryo screening can help patients prevent passing on recessive ataxia to their children.

If you would like to know more trinucleotide repeat expansions, you can look at our past Snapshot on Polyglutamine Expansion.

If you would like to learn more about carrier and embryo screening, take a look at these resources by the American College of Obstetricians & Gynecologists and Integrated Genetics.

Snapshot written by Eder Xhako and edited by Larissa Nitschke.

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An image representing survey results. Photo by Lukas on

Huntingtin: a new player in the DNA repair arsenal

Written by Dr. Ambika Tewari Edited by Dr. Mónica Bañez-Coronel

Mutations in the Huntingtin protein impair DNA repair causing significant DNA damage and altered gene expression

Our genome houses the entirety of our genetic material which contains the instructions for making the proteins that are essential for all processes in the body. Each cell within our body, from skin cells that provide a crucial protective barrier, immune cells that protect us from invading species and brain cells that allow us to perceive and communicate with the world contains genetic material. During early development in every mammalian species, there is a massive proliferation of cells that allows the development from a one-cell stage embryo to a functional body containing trillions of cells. For this process to occur efficiently and reliably, the instructions contained in our genetic material need to be precisely transmitted during cell division and its integrity maintained during the cell’s life-span to guarantee its proper functioning.

There are many obstacles that hamper the intricate and highly orchestrated sequence of events during development and aging, causing alterations that can lead to cell dysfunction and disease. Internal and external sources of DNA damage constantly bombard the genome. Examples of external sources include ultraviolet radiation and exposure to chemical agents, while internal sources include cell processes that can arise, for example, from the reactive byproducts of metabolism. Fortunately, nature has evolved a special group of proteins known as DNA damage and repair proteins that act as surveyors to detect erroneous messages. These specialized proteins ensure that damage to the DNA molecules that encode our genetic information is not passed to the new generation of cells during cell division or during the expression of our genes, ultimately protecting our genome. Many genetic disorders are caused by mutations in the genetic material. This leads to a dysfunctional RNA or protein with little or no function (loss of function) or an RNA or protein with an entirely new function (gain of function). Since DNA repair proteins play a crucial role in identifying and targeting mistakes made in the message, it stands to reason that impairment in the DNA repair process might lead to disease. In this study, Rui Gao and colleagues through an extensive collaboration sought to understand the connection between altered DNA repair and Huntington’s disease.

Blue strands of DNA
An artist’s rendering of DNA molecules.

Continue reading “Huntingtin: a new player in the DNA repair arsenal”