Identifying FDA-approved molecules to treat SCA6

Written by Dr Hannah Shorrock Edited by Dr. Larissa Nitschke

Pastor and colleagues identify FDA-approved small molecules that selectively reduce the toxic polyglutamine-expanded protein in SCA6.

Selectively targeting disease-causing genes without disrupting cellular functions is essential for successful therapy development. In spinocerebellar ataxia type 6 (SCA6), achieving this selectivity is particularly complicated as the disease-causing gene produces two proteins that contain an expanded polyglutamine tract. In this study, Pastor and colleagues identified several Food and Drug Administration (FDA) approved small molecules that selectively reduce the levels of one of these polyglutamine-containing proteins without affecting the levels of the other protein, which is essential for normal brain function. By using drugs already approved by the United States Food and Drug Administration to treat other diseases, referred to as FDA-approved drugs, the team hopes to reduce the time frame for pre-clinical therapy development.

SCA6 is an autosomal dominant ataxia that causes progressive impairment of movement and coordination. This is due to the dysfunction and death of brain cells, including Purkinje neurons in the cerebellum. SCA6 is caused by a CAG repeat expansion in the CACNA1A gene. CACNA1A encodes two proteins: the a1A subunit, the main pore-forming subunit of the P/Q type voltage-gated calcium ion channel, as well as a transcription factor named a1ACT.

The a1A subunit is essential for life. Its function is less affected by the presence of the expanded polyglutamine tract than that of a1ACT. The transcription factor, a1ACT, controls the expression of various genes involved in the development of Purkinje cells. Expressing a1ACT protein containing an expanded polyglutamine tract in mice causes cerebellar atrophy and ataxia. While reducing levels of the a1A subunit may have little effect on SCA6 disease but impact normal brain cell function, reducing levels of a1ACT may improve disease in SCA6. Therefore, Pastor and colleagues decided to test the hypothesis that selectively reducing levels of the a1ACT protein without affecting levels of the a1A protein may be a viable therapeutic approach for SCA6.

Colorful pile of medicines in blister packs which color are White, Yellow, Black and Pink pills.
By using drugs already approved by the FDA, the team hopes to reduce the time frame for pre-clinical therapy development. Photo used under license by Wanchana Phuangwan/
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A New Use for Old Drugs

Written by Dr. Amy Smith-Dijak Edited by Logan Morrison

Basic biology helps identify a new treatment for ataxia

Drug design doesn’t always have to start with a blank slate. Sometimes understanding how existing drugs work can help researchers to design new ones, or even to recombine old drugs in new and more effective ways. That’s what the researchers behind this paper did. They investigated the basic biology of three existing drugs: chlorzoxazone, baclofen, and SKA-31.

Two of these – chlorzoxazone and baclofen – are already FDA-approved for use as muscle relaxants, and chlorzoxazone had previously been found to have a positive effect on eye movements in spinocerebellar ataxia type 6. Looking at the results of their experiments, they realized that a combination of chlorzoxazone and baclofen would probably be an effective treatment for ataxia over a long period. They offered this drug combination to patients, who had few adverse effects and showed improvement in their diseasesymptoms. Based on these findings, the researchers recommended that larger trials of this drug combination should be conducted and that people trying to design new drugs to treat ataxia should try to interact with the same targets as chlorzoxazone.

mutliple types of drugs in pill form scattered ac
Can old drugs have potential for new types of treatment? Photo by Anna Shvets on

When this paper’s authors started their research, they wanted to know more about how ataxia changes the way that brain cells communicate with each other. Brain cells do this using a code made up of pulses of electricity. They create these pulses by controlling the movement of electrically charged atoms known as ions. The main ions that brain cells use are potassium, sodium, calcium and chloride. Cells control their movement through proteins on their surface called ion channels which allow specific types of ions to travel into or out of the cell at specific times. Different types of cells use different combinations of ion channels, which causes different types of ions to move into and out of the cell more or less easily and under different conditions. This affects how these cells communicate with each other.

For example, a cell’s “excitability” is a measure of how easy it is for that cell to send out electrical pulses. Creating these pulses depends on the right ions entering and exiting the cell at the right time in order to create one of these pulses. Multiple types of spinocerebellar ataxia seem to make it difficult for Purkinje cells, which send information out of the cerebellum, to properly control the pattern of electrical signals that they send out. This would interfere with the cerebellum’s ability to communicate with the rest of the brain. The cerebellum plays an important roll in balance, posture and general motor coordination, so miscommunication between it and the rest of the brain would account for many of the symptoms of spinocerebellar ataxias.

Earlier research had found a link between this disrupted communication and a decrease in the amount of some types of ion channels that let potassium ions into Purkinje cells. Thus, this paper’s authors wanted to see if drugs that made the remaining potassium channels work better would improve Purkinje cell communication.

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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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