VEGF-mimicking nanoparticles improve SCA1 disease phenotype in mice

Written by Dr. Chandrakanth Edamakanti Edited by Dr. David Bushart

VEGF nanoparticles offer a new avenue for developing treatments for SCA1 and other neurodegenerative disorders

Spinocerebellar ataxia type 1 (SCA1) is a neurogenerative disorder with symptoms that typically begin in the third or fourth decade of life. The disease is characterized mainly by motor incoordination that becomes progressively worse with age. Eventually, patients succumb to the disease about fifteen years after onset due to breathing problems. SCA1 is known as a “polyglutamine expansion” disorder, which means it is caused by a glutamine-rich region of a protein becomes abnormally large due to a genetic mutation. In SCA1, the polyglutamine expansion occurs due to a mutation in the ataxin-1 gene (ATXN1), causing the subsequent ataxin-1 protein to have abnormal functions.

Previously, a research team led by Dr. Puneet Opal found that the levels of a protein called VEGF (vascular endothelial growth factor) is reduced in cerebellum of a mouse model of SCA1. The team was able to improve disease symptoms in these mice by restoring VEGF protein levels using two different methods: i) by crossing the SCA1 mice with another strain of mouse that expressed high levels of VEGF, and ii) delivering recombinant protein (rVEGF) into the brains of SCA1 mice (Cvetanovic M et al 2011). However, the researchers noted that it would be challenging to implement the rVEGF delivery strategy for clinical therapy, since one would need to overcome the extreme financial cost and difficulty that comes with using recombinant proteins.

stethoscope and blood pressure cuff
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VEGF is crucial for maintaining the microvasculature (small arteries and veins) in the brain and also supports neuronal health and regeneration. Current evidence suggests that VEGF therapy could be beneficial for several neurodegenerative conditions such as stroke, Alzheimer’s disease, Parkinson’s disease, and ALS. Unfortunately, significant impediments have prevented the translation of recombinant VEGF therapy to the clinic. In a recently published ‘Brain’ research article, Dr. Opal and his team sought to address this obstacle by exploring a potential low-cost VEGF treatment strategy known as VEGF peptide mimetics. These peptide mimetics are smaller and simpler molecules that mimic biological compounds; in this case, VEGF. Peptide mimetics are typically smaller than the original molecule (small enough to be considered “nanoparticles”), which helps limit side effects and makes delivery to the target much easier than using recombinant proteins like rVEGF.

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Snapshot: What is the Cerebellum?

The cerebellum, often referred to as the “little brain”, is part of the brain that is located behind the cerebrum (forebrain). The cerebellum accounts for about 10% of the brain’s volume. Despite occupying a small volume, the cerebellum contains more than half of the neurons in the brain. Most of the evolutionary research with respect to the brain has been focused on the forebrain; however, recent evidence suggests that the expansion of the size of the cerebellum might have given humans an edge with respect to higher behavioral functions, such as the use of tools. Therefore, the cerebellum has played a vital role during evolution, and this suggests an indispensable function for the human cerebellum.

cartoon diagram of the human brain, with the cerebelum coloured in pink
Diagram of the human brain, with the cerebellum highlighted in pink. Picture courtesy of Wikimedia Commons.

What does the cerebellum do?

For several decades, scientists believed that the main role of the cerebellum was to maintain posture and balance, to fine-tune motor movements, and to enforce motor learning. If you think about performing a certain movement (these thoughts happen in the forebrain), the cerebellum compares these “movement plans” with what movements were actually made and corrects for errors if there were any. This fine-tuning makes movements precise and is critical for making voluntary movements such as walking, running, or speaking. Therefore, it is with the help of the cerebellum that we learn to get better at throwing a curveball, riding a bike, or learning any other complex motor tasks.

Is that all the cerebellum does?

Well, scientists used to think so. Over the past two decades, new evidence has made scientists to re-evaluate their thoughts about the cerebellum. Scientists now believe that the role of the cerebellum extends beyond fine-tuning motor movements, and likely includes cognitive functioning and certain reward-seeking behaviors. However, this aspect of cerebellar function is still being studied and there is a lot for scientists to uncover.

What happens when the cerebellum is damaged?

The cerebellum is one of the primary culprits in many types of cerebellar ataxia, where the damaged cerebellum forces the affected individuals to gradually lose their ability to walk. Therefore, it is imperative to better understand how the cerebellum contributes to ataxia to provide better treatment for patients. Apart from ataxia, the cerebellum may also contribute to other disorders such as dystonia, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and autism spectrum disorders. Therefore, understanding what happens when the cerebellum goes awry is critical for improving the quality-of-life for patients all over the globe.

If you would like to learn more about the cerebellum, take a look at these resources by the Khan Academy and

Snapshot written by Dr. Sriram Jayabal and edited by Dr. David Bushart.

Snapshot: What are Mouse Models?

If you are thinking of a dressed-up mouse walking on a ramp and posing for pictures, then you are thinking wrong! Mouse models – as the name indicates – serve as a “model” for human diseases. Mice, similar to many mammals, can develop diseases. These include cancers, diabetes, and cardiovascular problems. Over the past century, mice have been used to study not only these naturally-occurring mouse diseases, but also disorders which do not typically affect mice. For instance, thanks to advancements in genetic engineering, scientists have generated mice that develop Alzheimer’s disease and cystic fibrosis. These mouse models are then used as tools to help scientists study the underlying causes of human diseases and, ultimately, create better treatments.

gloved hands holding a white mouse with red eyes
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Why can’t we study the disease in humans?

In humans, we can only obtain a snapshot of disease at a given time. This is particularly true for neurodegenerative diseases, where one cannot simply isolate parts of the brain to study them. In addition, an individual suffering from neurodegenerative disease is often not aware of their condition – and are not even diagnosed – until they are symptomatic. As a result, it is impossible to understand how an individual developed the disease over time, which can make it quite difficult to determine a proper therapeutic course. To best understand the cause and progression of neurodegenerative disorders, researchers generate animal models. These models, often using mice, are informed by genetic susceptibility and environmental risk and mimic the clinical course of a human disease.

Why use a mouse as a model?

There are several advantages to using the mouse as a model:

  • Humans share more than 95% of their genome with mice, which means disease-causing mutations in mice have an effect that is similar to what occurs in human disease.
  • The mouse genome is well-studied and completely mapped (i.e., all genes have been identified), which makes it easier for researchers to manipulate genes in mice to study most human diseases.
  • The life span of mice is short, which allows the disease to be studied at an accelerated pace.
  • The size and ease in handling of mice makes preliminary testing of potential drug treatments a fairly simple process.
  • The maintenance of mouse models is much cheaper than larger organisms.

Why are mouse models vital?

Mouse models are indispensable for a better understanding of human disease and for the development of effective treatments. Mouse models of deafness, for instance, have played a vital role in identifying the specific genes that are responsible for inherited hearing loss. Similarly, mouse models have also enabled scientists to model complex neurological diseases such as Alzheimer’s disease, Huntington’s disease, and several different types of ataxia. These models have greatly improved our understanding of neurodegenerative disease and brought us one step closer to the development of effective treatments. Because of this, the quest to identify a mouse model that mimics every aspect of a human disease – such as a specific type of spinocerebellar ataxia – continues to this day. These mice are instrumental for scientists to develop new treatments for disease and, ultimately, a cure.

If you would like to learn more about mouse mondels, take a look at these resources by the Jackson Laboratory and National Institutes of Health.

Snapshot written by Dr. Sriram Jayabal edited by Dr. Maxime Rousseaux

Thrift Store Pharmacy: Repurposing a Multiple Sclerosis drug for use in SCA6

Written by Anna Cook Edited by Dr. Monica Banez

Researchers successfully use an existing multiple sclerosis drug to improve performance in an SCA6 mouse model

Spinocerebellar ataxia type 6 (SCA6) is a rare hereditary movement disorder affecting 5 of every 100,000 people worldwide1. The disease is caused by the expansion of a repeating DNA sequence in the CACNA1A gene. The length of this repeat, which is made up of sequential iterations of the code CAG, is normally variable in length, stretching between 4 and 18 repeats in the healthy population. However, in SCA6 patients, something goes wrong and the CAG repeat in the CACNA1A gene is expanded to have 21-33 repeats, causing dysfunction in the brain and motor symptoms for reasons that are not yet fully understood. SCA6 belongs to the group of disorders called polyglutamine diseases, all of which are caused by CAG expansions in different genes. These include disorders like Huntington’s disease and other spinocerebellar ataxias.

five laboratory mice on a rotarod device to test their balance
Laboratory mice on a rotarod device to test motor coordination skills, similar to one of the experiments conducted in this study. Image courtesy of WikiMedia.

SCA6 onset generally occurs at middle age. The characteristic symptoms are difficulties with motor coordination that progressively get worse as patients get older. Current treatment options are limited to managing symptoms rather than addressing the cause of the disease. However, researchers have recently discovered that the FDA-approved drug 4-AP reduces motor symptoms in a mouse model of SCA6, making the drug a promising candidate for the treatment of the disease in humans.

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Snapshot: What are Clinical Trials?

How does a medical drug get to patients?

Research is being done every day to discover new or better ways to treat diseases and various medical conditions. In order to determine if these treatments will help patients, studies known as “clinical trials” need to be done before these methods of intervention can be safely and widely used in human patients. Clinical trials are regulated studies that involve volunteer human participants to test how safe and effective a potential new treatment.

doctor writing notes
Physician writing clinical notes. Photo by Pexels.

Treatment interventions being tested can range from medical drugs, to medical devices, to introducing lifestyle changes (diet, exercise). Most clinical trials test new drugs by comparing them to no treatment, to an inactive version of a drug known as a “placebo”, or to a currently available approach. Clinical trials may take months to years to complete and are conducted in a series of steps, known as “phases”, described below.

Phase 1: Is the drug safe?

Healthy volunteers receive different doses of the drug and side effects are evaluated. Safe doses are chosen based on research performed prior to Phase 1, or “pre-clinical research”. The goal is to make sure the drug is not harmful. Usually lasts a few months.

Phase 2: Is the drug effective?

Similar to Phase 1, but the drug is given to a small group of volunteers affected by the medical condition it is intended to treat. This is commonly done by comparing how well participants do with the new drug compared to a placebo. Participants and doctors are typically “blinded”, or prevented from knowing whether the patient received the active drug or the placebo. This is meant to allow for unbiased observations of the participant’s health in response to the drug. Usually lasts a few months to years.

Phase 3: Is the drug still safe? Is it doing what is needed?

Testing becomes a bit more complex. The participant population is expanded while safety and efficacy of the drug continues to be tested. More detailed information about the drug as a treatment is gathered in this phase. Usually lasts several years.

Phase 4: The drug is approved and available on the market.

Long-term effects of the drug will continue to be monitored by pharmaceutical companies and compared to other available drugs and therapies for cost and efficacy.

If you would like to learn more about clinical trials, take a look at these resources by and CenterWatch.

Snapshot written by Dr. Claudia Hung edited by Dr. Judit M. Perez Ortiz.