Seed Money Grants

Adam Vogel, PhD
Centre for Neuroscience of Speech
Parkville, Victoria, Australia

Intensive home based speech rehabilitation for adults with degenerative ataxia

Loss of ability to speak is a devastating and inevitable outcome of many neurodegenerative diseases. When people lose their ability to speak, they lose their ability to carry out basic tasks. They can be stigmatized and marginalized, and they often have challenges with employment. In time, they experience a decrease in their quality of life. Hereditary ataxias cause a lack of coordination with gait, speech, and eye and hand movement. No therapies are currently available to stop degenerative ataxia from progressing. However, therapy to improve speech is within reach.

My team and I have conducted a successful pilot study that draws on (1) the principles of motor learning and biofeedback and (2) the expertise of a team that specializes in movement therapy and ataxia. We have designed a home-based, intensive 4-week speech exercise program designed to improve speech in patients with hereditary ataxia. The treatment focuses on improving intelligibility and vocal control. We created exercises and feedback to enhance individuals’ ability to monitor their own speech abilities and improvements. The program is suitable for use in a clinical setting, so it can readily be brought into clinical practice. It can also potentially be adapted for a range of other progressive neurological disorders. Funding from the National Ataxia Foundation will be used to develop a controlled, well-designed study that can assess the effectiveness of this program.

 

Margit Burmeister, PhD
University of Michigan, Ann Arbor, MI

Role of VPS13D in Ataxia
 

Many different genes can be at play in causing ataxia to develop. To date, more than 70 genes are known to cause ataxia when they are mutated. But in many individuals and families, no mutations in known ataxia genes can be found. This finding suggests that many more genes still need to be identified to help these affected families and to fully understand the causes of their type of ataxia.

My team and I have recruited a large nuclear family of 14 siblings, 5 of whom are affected with an adult onset form of ataxia. The ataxia has caused degeneration of the cerebellum, nerve damage in other parts of the body, and issues with eye movement, but it has not caused cognitive impairment. Because neither the parents of the affected individuals nor any of their children are affected, the inheritance of the ataxia appears to be recessive. As a result, we expect to find ataxia-causing mutations in both copies of the gene—the one inherited from father’s side and the one inherited from the mother’s side.

Genetic analysis has narrowed the location of the gene to a small interval (stretch of nucleotides) on chromosome 1. Using new genetic sequencing methods, we have identified a likely cause of ataxia in this family in that interval on chromosome 1. All of the individuals affected with ataxia have two mutations in the VPS13D gene, but the individuals without ataxia have no or only one mutation. In this study, we will be conducting experiments in hopes of establishing VPS13D as a new ataxia gene. We already have neurons from affected and unaffected family members, and we also have fruit flies that are missing the fruit-fly equivalent of the VPS13D gene.

We will first determine whether neurons generated from affected and unaffected family members show differences in VPS13D compared with normal cells. In the fruit flies, we will then determine if there are neurological impairments in flies that lack the fly equivalent of VPS13D. (We have previously studied flies to demonstrate how ataxia genes present themselves in the human body.) Finally, by comparing how the normal and the mutant versions of the gene function in the fruit fly system, we plan to show that the specific amino acid change found in the human family is damaging. If we find that the mutant form of VPS13D does cause ataxia in humans, we expect to discover that this mutant form will not be as effective as the normal form of VPS13D in the fly system.


Fang He, PhD
Texas A&M University, Kingsville, TX

Development of a Drosophila model for Spinocerebellar Ataxia type 36 (SCA36)
 

Ataxia of the cerebellum is commonly caused by expanded repeat sequences of DNA—the abnormal over-repetition of DNA sequences. For example, spinocerebellar ataxia type 36 (SCA 36) is a type of cerebellar ataxia caused by a repeat expansion of the six-letter string of nucleotides, GGCCTG. In people without ataxia, only about 3 to 14 repeats of this string of nucleotides appear. But in people with SCA36, the GGCCTG sequence repeats hundreds of times. Although we know that people with SCA36 have expanded repeats of GGCCTG, no one knows exactly how that repetition damages neurons. To better determine how expanded repeat sequences lead to SCA36, my team and I will use genetically modified fruit flies (Drosophila melanogastre) that have expressed up to 100 GGCCTG repeats. Through our research, we will learn more about whether these expanded repeats are themselves toxic to the neurons. By learning how these DNA mutations lead to neuron damage, we hope to shed light on how therapies could target and possibly halt the excessive expression of GGCCTG repeats.

 

Clara Van Karnebeek, MD, PhD
University of British Columbia, Vancouver, BC, Canada

Whole Exome Sequencing in the Diagnosis and Management of Atypical Childhood Hereditary Ataxia Conditions
 

The National Ataxia Foundation (NAF) was formed by John and Henry Schut in 1957 to promote awareness of the degenerative ataxias, support research into the causes and cure of the disease, and provide support and comfort to ataxia patients and their families. We are resolved to advance these primary objectives through our project “WES in Atypical Childhood Ataxia.”

New technologies have drastically changed the way we diagnose rare diseases. The human genome contains about 3 billion bases or letters. For over a decade, researchers have had the ability to read a person’s entire genome through a process called whole genome sequencing (WGS). However, we were not able to translate the DNA code into information that we could meaningfully use (for example, for treatment or predicting risk of disease). Now, through testing known as whole exome sequencing (WES), we can now focus in on the “coding” portion of the genome, called the exons, that provides instructions for making proteins. WES methods allow the body’s entire set of instructions—or exome—to be examined as a single laboratory test—rather than having to individually analyze all 20,000 genes that make up our exome. Through WES, we are able to look for “spelling mistakes” (known as pathogenic mutations) in gene(s) and then determine if these changes are the cause for the person’s illness.

With this innovative tool, we aim to enroll and offer WES to 12 children with severe or complex ataxia in order to (1) discover new genes that cause ataxia, (2) expand what we understand about the clinical picture of known human genes that cause ataxia (3) make sense of these rare genetic ataxic conditions at a microscopic “molecular” level so that we can understand, target, treat and potentially cure these disorders. We plan to achieve these goals by merging our center’s unique expertise in combining deep characterization of a patient’s clinical picture (combined physical, neurological and metabolic symptoms) with expertise in WES analysis. Our hope is that this focused study of ataxic cases at our center will positively affect the lives of patients and families, forge the discovery of new genetic ataxia disorders, expand descriptions of known conditions and create new treatment opportunities.

 

Martin Lavin, PhD
University of Queensland Centre for Clinical Research (UQCCR) Australia

Assessing the role of senataxin in cellular inflammation, gene regulation, and innate immunity in Setx-/- mice and a human neuronal model
 

Ataxia oculomotor apraxia type 2 (AOA2), a progressive form of cerebellar ataxia, is a neglected rare neurological disorder that develops mostly in late adolescence to early teens. AOA2 occurs from mutations in the SETX gene. The SETX gene encodes the senataxin protein, which plays a key role in the response to DNA damage and regulation of gene expression. Although researchers have described many mutations in the SETX gene, we know very little about the mechanism of disease progression, and no specific treatment exists for AOA2. Currently, the primary way to manage the disease is to provide supportive care (care that does not treat the disease but instead keeps the patient comfortable).

In 2015, while collaborating with Dr Ivan Marazzi at Columbia University, our research team described an unanticipated role that senataxin plays in controlling innate (natural) immunity, the part of the immune system that responds immediately when a toxin or other foreign substance appears in the body. The involvement of senataxin in innate immunity offers new insight into a possible link between neurodegenerative disorders and inflammation. This finding provides a new framework to explore more fully the possibility that infection and a de-regulated innate immunity may contribute to the development of AOA2—and potentially other neurodegenerative disorders. The purpose of this research project is to assess the role of senataxin in cellular inflammation, gene regulation and innate immunity. Our aim is to gather more knowledge of the how AOA2 begins and then progresses. Specifically, we want to better understand the molecular changes that are involved in AOA2—by (1) further narrowing down the role of senataxin in innate immunity and (2) identifying critical genetic and cellular pathways that are involved in the development of the disease. Advancing an understanding of the cellular function of senataxin and its role in the disease process for AOA2 will be key as researchers help develop effective therapy for patients who have AOA2.

 

Susan Perlman, MD
UCLA, Los Angeles, CA

Web-based National Ataxia Database
 

The National Ataxia Registry, the National Ataxia Database, and the Ataxia Tissue Donation Program were formed to provide the infrastructure for clinical research in the ataxic disorders. They enabled ataxia researchers to notify ataxia patients of upcoming research projects, to store and analyze data from those projects, and to examine tissues from ataxia patients to find out how ataxia develops and how the body responds to it.

The web-based National Ataxia Database is currently housed on the UCLA computer servers, and over the years since its development, has provided natural history database support to the UCLA Ataxia Clinic, as well as to the Ataxia Clinic at John Hopkins University. Other "Ataxiologists" in California, Arizona, Nevada, and Colorado have expressed interest in using it as well. It has begun to provide a platform to support and join specialists in clinical care and clinical research of ataxia. It will ultimately assist all members of the Ataxia Clinical Research Consortium in future collaborative endeavors in clinical research and in setting standards for clinical care.

Following the end of funding from the National Institutes of Health for the Rare Disease Network, with of the help of the NAF "bridge" grant, we were able to continue to import the existing data of the natural history study into the National Ataxia Database. This allowed us to continue enrollment and follow-up of participants in this important study of SCA l , 2, 3, and 6. Data collection will begin on participants with SCA 7, 8, and 10. There are now 13 sites contributing to this project, and six more will be added. Close to 500 participants have been enrolled and are pursuing natural history examinations and banking of specimens.

The National Ataxia Database will also be open for ataxia researchers to "bank" other clinical data collected, either in the individual's private data docks (not accessible to other ataxia researchers) or in data docks shared by several researchers. (e.g., for a proposed project to look at coded clinical data on people with sporadic ataxia). Templates will be added for scales to measure fatigue, dizziness, cognition, and neuropsychiatric symptoms. The National Ataxia Database is an essential tool for the Clinical Research Consortium for the Study of Cerebellar Ataxia.

 

Gulin Oz, PhD
University of Minnesota, Minneapolis, MN

Launching the US-Europe Neuroimaging Partnership in SCA
 

A major challenge in developing therapies for spinocerebellar ataxias (SCAs) has been the lack of highly accurate imaging markers for (1) detecting changes due to SCA in the cerebrum and cerebellum and, consequently (2) evaluating the effectiveness of treatments being studied. Although researchers have developed clinical scales that can be used to assess response to treatment, they have several limitations. One important limitation is that results can be highly variable. Therefore additional non-invasive imaging tests are still needed to measure the direct effects that potential treatments have on the brain. In this project, we will bring together two ongoing efforts in the United States and Europe to validate imaging markers for SCA3.

SCA3 is the most common SCA in the world and affects about 30% of all families with a history of dominant ataxia. Currently, there is no causal treatment for SCA3. However, as we continue to understand the way that SCA3 progresses at the cellular level in the body, several new treatment approaches are being or will be tested in clinical trials. To ensure strong outcomes from these trials, we wish to take advantage of an ongoing, NIH-supported imaging study that focuses on chemical markers of SCA3. We intend to add a magnetic resonance (MR) imaging component to that study so we can get detailed structural and functional MR data, which will also be part of an ongoing European study called the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI). Funds from the NAF Research Grant will allow us to initiate a US-Europe imaging collaboration that is long overdue. This collaboration can help validate noninvasive MR biomarkers for upcoming SCA3 trials taking place in many sites throughout the world.

 

Sandra de Macedo Ribeiro, PhD
Instituto de Biologia Molecular e Celular
Porto, Portugal

New therapeutic approaches for Machado-Joseph Disease: Chaperoning protein self-assembly
 

Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease, is a rare neurodegenerative disease. No therapy is currently available for SCA3. SCA3 is caused by an expanded stretch of CAG triplets in the affected gene. The overrepetition of CAG causes a protein called ataxin-3 to form abnormally—and in a way that is toxic to neurons.

For the past 20 years, researchers have made impressive progress in understanding the cellular functions and formation of ataxin-3, but so far no specific treatments are available for SCA3. We need to better understand the three-dimensional structure of ataxin-3 to fully determine its function and dysfunction at the molecular level. By understanding more clearly how ataxin-3 becomes toxic, we can also learn how to develop targeted therapies. We propose to study a number of synthetic molecules that can bind and reshape ataxin-3 into a non-toxic form. If we can determine how ataxin-3 is shaped with atomic precision, we can hopefully identify which molecules can serve as the best therapy to treat the dysfunction.

 

Ana Teresa Antunes Simões, PharmD, PhD
University of Coimbra, Portugal

Calpain-mediated proteolysis in Machado-Joseph disease
 

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most frequent worldwide autosomal dominantly-inherited ataxia, which means that affected individuals have a 50% chance of transmitting the affected gene to their children.

In MJD, a mutation leads to a bigger-than-normal stretch of polyglutamine at the ataxin-3 protein. The ataxin-3 protein is a biological molecule that is important for cellular quality control. Researchers believe that ataxin-3 is cut into smaller fragments. Our research team and others have recently shown that the molecules responsible for the breakdown of ataxin-3 are called calpains. Calpains form toxic fragments, move the ataxin-3 from the cytoplasm to the nucleus, and contribute to degeneration of neurons.

The aim of this project is to understand, at a cellular level, calpains’ contribution to the development of MJD. To achieve this aim, we will evaluate how genes encode the calpain system, determine in which places ataxin-3 is cut, and how calpains are activated according to the different brain regions, cell types and timeline for disease progression. Moreover, because no current treatment is available, we will evaluate whether a novel calpain inhibitor can reduce cell injury and alleviate loss of motor coordination. These expected results could be used to develop a therapy for MJD patients in a short-time frame. The results can also be used to identify biological measures, or markers, of MJD progression or treatment response. Furthermore, understanding the calpains’ role in MJD can inform our understanding of other ataxias that are vulnerable to calcium deregulation.