Hi everyone! This is a quick message from the volunteers behind SCAsource. About a year ago we conducted a feedback study to ask what we were doing well and what we could change or improve. Some of the changes we hoped to introduce back in the spring were delayed due to COVID-19.
But we are so excited to introduce to you one of the changes we are making! We are adding a new article type: SCAsource Spotlights.
One of the things you told us you wanted to know more about was who is doing ataxia research. What labs exist? Where are they located? What questions are they asking? Who are these researchers?
SCAsource Spotlights will be able to shed some light on this. They will be short profiles of ataxia laboratories around the world. In addition to what science is going on in these labs, each Spotlight will also include a fun fact about something that makes that research group unique.
Please let us know how you like this new article type! Our first Spotlight will be on the Watt Lab from McGill University in Montreal, Canada!
If you are from an ataxia lab and want us to do a Spotlight on you, please get in touch with us through our contact page.
Drug delivery into the body can be achieved in several ways, from applying a medicated cream on the skin, to swallowing a pill, to injecting into a muscle or vein. Each route of delivery should at least achieve one thing – getting the drug to the part of the body where it can be helpful. Delivering therapeutic drugs into the brain, however, can be more difficult. Intrathecal injections are used to overcome this challenge.
When a drug enters the body, it travels through the bloodstream until it reaches the target organs. But when a drug is destined to reach the brain, it needs to pass through a unique security feature known as the blood-brain barrier. The blood-brain barrier is important for keeping harmful and unknown substances out of the brain. It turns out that the majority of drugs injected into the body cannot pass this barrier. This poses a challenge for researchers and doctors for delivering important drug treatments to the brain.
One way that drugs can be delivered to the brain via the blood is by modifying their chemical nature slightly. This can help with entry through the blood-brain barrier. A more straightforward route of delivery is by injecting drugs into the brain space directly. Your brain inside your head and spinal cord along your back are bathed in and float in a liquid called cerebrospinal fluid (CSF).
CSF is a clear, colourless fluid that protects the brain from injury by absorbing shock, and it helps bring waste products out of the brain. Importantly, as CSF flows, it helps distribute substances around the brain. Injecting a drug directly in the CSF allows that drug to bypass the blood-brain barrier. One of the less invasive ways to access the CSF space is via injection through the thecal sac, the cushiony layer containing CSF that surrounds the spinal cord. This type of injection is therefore known as an “intrathecal injection”.
Intrathecal injections can be very helpful. They are used during surgeries to manage pain (spinal anaesthesia) and to deliver chemotherapeutic agents to target brain cancers. Intrathecal injections becoming an increasingly important route of administration for drugs investigated in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, ALS, spinal muscular atrophy (SMA), and spinocerebellar ataxias (SCAs). These drugs include antisense oligonucleotides that can be delivered directly to the brain.
However, there are still a few challenges in giving medication through intrathecal injections:
Medication delivered by intrathecal injections may need to be given quite often. Since the CSF is replenished regularly, the substances are cleared quickly out of the brain and spinal cavity.
Intrathecal injections involve a needle being inserted into the spine. So they are more invasive and painful than a typical shot or swallowing a pill. This is especially true if multiple injections are needed.
Therefore, researchers and doctors are constantly trying to learn more about how drugs enter the brain. By studying this, they will make improvements in how medication is delivered to patients. Despite these challenges though, intrathecal injections are a clever and important way for delivering critical drugs to the brain to treat a wide range of diseases.
Blood circulates throughout the body in tubes called blood vessels, delivering oxygen and essential nutrients to different organs. However, not all things that circulate through the body can get into the brain. The blood vessels of the brain are slightly different. Their walls have a unique barrier that allows entry of some substances, but keeps others out of the brain. This unique security feature is known as the blood-brain barrier. This barrier allows passage of some substances, but can block out others. This is important because this provides access to substances that the brain needs to function, while keeping harmful substances at bay. The blood-brain barrier is therefore an important feature that keeps our brains and bodies healthy.
How does the blood-brain barrier work?
The blood-brain barrier is the result of the coordinated effort of several players working together at a microscopic level. These players form physical and functional barriers to select what can enter or exit the brain. Like other blood vessels in the rest of the body, blood vessels in the brain are lined with a thin wall of cells called endothelial cells. Between these endothelial cells, there are gaps that can allow substances to exit the blood to the various organs in the body. However, in the brain, these cells form tight connections between the gaps to restrict large molecules from passing through.
Additionally, brain cells called astrocytes and pericytes wrap around endothelial cells to more strictly block what substances can get through. Very small molecules, such as hormones, can slip through this complex wall. Larger molecules, such as sugars, water, amino acids, and insulin, require help from proteins known as transporters to get through, and are a critical component of the blood-brain barrier.
What happens if the blood-brain barrier is not working properly?
Infections, abnormal inflammation, or prolonged stress in the body can contribute to larger gaps between the tight connections of the blood-brain barrier, seen in diseases such as multiple sclerosis or Alzheimer’s disease or with brain tumours. If the blood-brain barrier is not working properly, harmful substances that are usually kept out of the brain may enter and cause problems, and can start a harmful cycle of more infections and more inflammation.
What challenge does the blood-brain barrier post for brain therapies?
The blood-brain barrier is critical for regulating what enters or exits the brain to maintain a healthy brain. However, the blood-brain barrier also poses a challenge for researchers. Many potentially life-saving drugs developed for treating brain diseases and brain injury cannot pass through this barrier. To overcome this, scientists have devised novel ways to directly or indirectly deliver drugs into the brain. The therapeutic potential of smaller sized drugs (often called “small molecules”) is intentionally being tested as they can more easily pass from the blood to the brain.
Another alternative is making previously impenetrable drugs better at entering the blood-brain barrier. Scientists are trying to do this by attaching chemical modifications that “escort” them into the brain. Finally, direct access to the brain is created by injections that allow access to the brain space. We will talk more about this topic in our Snapshot on Intrathecal Injections next week!
Written by Dr. Marija Cvetanovic Edited by Dr. Ronald Buijsen
Researchers from the University of California show they can “edit” the Frataxin gene in human cells from Friedreich’s Ataxia and transplant them into mice. This lays the groundwork for this method to be tested for safety.
Friedreich’s ataxia is a progressive, neurodegenerative movement disorder. It is often associated with heart issues and diabetes. Symptoms first start to appear in patients when they are around 10 to 15 years old. Friedreich’s ataxia has the prevalence of approximately 1 in 40,000 people and is inherited in a recessive manner. This means that patients with Friedreich’s ataxia inherited a disease gene from both the father and mother. Friedreich’s ataxia is caused by an overexpansion of the GAA repeat in the Frataxin gene, all these extra repeats causes less Frataxin protein to be made.
Human hematopoietic stem and progenitor cells (HSPCs) are the stem cells that give make to other types of blood cells. You can find HSPCs in the blood all around the body.
HSPCs are ideal candidates for use in stem cell therapy because of a few reasons. First, you can easily get them out of the body through a blood donation (at least easier than some other types of cells!). Second, they can self-renew, meaning they will make more of themselves. Third, other folks have researched this type of cell before, so we know they are fairly safe. Researchers wanted to test if these cells could be used to help treat Friedreich’s ataxia.
Written by Dr Hannah Shorrock Edited by Larissa Nitschke
Repeat interruptions in SCA10 influence repeat tract stability and are associated with epileptic seizures
Multiple spinocerebellar ataxias (SCAs) are caused by repeat expansion mutations, but in some cases, these repeat expansions are interrupted. The presence of repeat interruptions can influence disease symptoms and how the repeat expansion behaves. This is the case for SCA10. Some patients with SCA10 have a series of repeat interruptions, which are referred to as an ATCCT repeat interruption motif. In SCA10 patients with this interruption motif, Dr. Ashizawa and his team found an increased risk of developing epileptic seizures and identified that the interruptions influence the local stability of the repeat expansion.
SCA10 is a dominantly inherited ataxia caused by an ATTCT repeat expansion in the Ataxin 10 gene (ATXN10). Unaffected individuals usually carry 9-32 ATTCT repeats, while SCA10 patients carry an expansion of up to 4500 repeats. SCA10 patients suffer from cerebellar ataxia, but some patients also have other symptoms, including epileptic seizures. Dr. Ashizawa and his team were interested in why some patients with SCA10 suffer from epileptic seizures, but others do not.
Initially, the group investigated whether the length of the ATXN10 repeat expansion correlated with epileptic seizures. They found no difference in repeat length between 37 SCA10 patients who developed epilepsy and 51 who did not. This shows that repeat length does not influence whether or not SCA10 patients develop epileptic seizures.