An Expanding View of Ataxia

A renowned clinical research program seeks new insights into ataxia and related disorders.

UT Southwestern’s Multidisciplinary Ataxia Clinic in the O’Donnell Brain Institute is a hub for research and care of patients with ataxia. This group of poorly understood, often disabling neurological disorders affects up to 150,000 people in the U.S., resulting in uncoordinated limb and trunk movements and falls, frequently leading to wheelchair confinement.

Led by Vikram Shakkottai, M.D., Ph.D., Associate Professor and Vice Chair for Basic Research in the Department of Neurology, as well as a member of the O’Donnell Brain Institute, the Multidisciplinary Ataxia Clinic is equipped to make important and needed strides in the diagnosis, study, and treatment of this difficult disease.

“We are building a truly comprehensive program with notable expansions across our clinical and

research components,” Dr. Shakkottai says. “Our providers really think deeply about a patient referred with ataxia, or labeled as having it, and revise a diagnosis if necessary. This label is, many times, incorrect.”

NO CLEAR FIX

While the etiologies of ataxia are diverse, recent advances have led to the discovery of novel genetic causes for ataxia and a more comprehensive understanding of the biological pathways critical for normal cerebellar function.

Importantly, when these molecular pathways become dysfunctional, patients develop ataxic symptoms, Dr. Shakkottai explains.

“The underlying causes of ataxia are incredibly diverse, ranging from infectious, immune-mediated, to genetic, and knowledge about the etiology of these disorders, even among neurologists, is poor,” Dr. Shakkottai says.

He adds that differentiating inherited causes from potential immune causes is vital to both avoid unnecessary treatment and to initiate appropriate treatment early. Historically, treatments for ataxia were thought to be ineffective, leaving many patients with ataxia untreated. In February 2023, the U.S. FDA approved the first drug specifically for the treatment of Friedreich’s ataxia. This therapy, called omaveloxolone (Skyclarys), works by counteracting the effects of Friedreich’s ataxia in nerve and muscle cells.

“Friedreich’s ataxia is a debilitating neuromuscular disorder that, over time, robs patients of their mobility and independence,” Dr. Shakkottai explains. “The recent approval of omaveloxolone represents the first disease-specific drug available for patients with this debilitating disease.”

JUMP-STARTING CARE

On the clinical side, patients in UT Southwestern’s Multidisciplinary Ataxia Clinic who are diagnosed with ataxia or a related disorder are provided sufficient information, in the right setting, to ensure they understand what the future holds for them and what approaches – both pharmacological and nonpharmacological – can resolve the etiology or symptoms of the disease.

Along with neurologists, the clinic also involves specialists in physical therapy, speech pathology, and occupational therapy to give patients broad-based care for the various aspects of their condition, which can include impairments of balance, speech, and hand dexterity. The clinic’s physical therapists can provide important input at the same time as clinical visits, a feature that is vital for patients with ataxia, who often travel long distances to receive expert treatment.

“Patients come from all over the country to receive care at the clinic,” Dr. Shakkottai says. “It’s incredibly humbling to know that we are one of the few ataxia programs – nationally or internationally – providing state-of-the-art clinical care.”

In addition, Dr. Shakkottai notes the availability of comprehensive genetic testing through the clinic. Because ataxia can be misdiagnosed as other neurodegenerative disorders, genetic testing is often useful for identifying the underlying cause. “Through genetic testing, families have been able to identify the cause of their ataxia. It has also been incredibly helpful in identifying treatable causes of the disorder, in predicting future disability, and in family planning,” he adds.

Currently, about 20% of genes in families with a dominant or recessive pedigree remain undiscovered, Dr. Shakkottai explains, anticipating that genetic testing of patients in the clinic will provide information for novel gene discoveries.

BECOMING A HUB FOR RESEARCH

The Multidisciplinary Ataxia Clinic is also becoming a global hub for research. Dr. Shakkottai is currently leading a multi-institutional, longitudinal, observational study of participants with inherited ataxia that he previously initiated at the University of Michigan.

Dr. Shakkottai also conducts clinical and laboratory research on a mission to determine whether alterations in neuronal physiology contribute to motor dysfunction and to translate preclinical mouse model research to human clinical trials for cerebellar ataxia.

Recent work in his laboratory has identified shared dysfunction in the cerebellum in mouse models of ataxia, with identification of several ion channels that act in concert, converging on large-conductance calcium-activated potassium channels.

“Basic research into mechanisms of disease and development of therapy is an important endeavor for UT Southwestern’s ataxia program,” he says.

To further research progress, UT Southwestern recently recruited Marek Napierala, Ph.D., an Associate Professor of Neurology, whose research interests include understanding the molecular mechanisms of Friedreich’s ataxia.

Additionally, Elan Louis, M.D., M.S., Chair of Neurology at UT Southwestern, is renowned for his study of cerebellar anatomical changes in tremor. With six faculty members within the department studying various aspects of cerebellar impairment, UTSW has one of the largest groups of cerebellar researchers in the country.

AN EXPANDING VIEW OF FRATAXIN DEFICIENCY

New research published in Human Molecular Genetics by Dr. Napierala and colleagues has uncovered new mechanistic insights into the pathogenesis of Friedreich’s ataxia.

“Friedreich’s ataxia is an autosomal recessive disease primarily caused by biallelic expansion of the guanine-adenine-adenine (GAA) trinucleotides located in intron1 of the FXN gene,” Dr. Napierala explains. “In most patients, frataxin – the protein encoded by the FXN gene – does not carry any mutations; instead, the severe decrease of its levels leads to this progressive multisystem disorder.”

Dr. Napierala notes that a block in transcription progression caused by expanded GAA repeats has been recurrently proposed as the mechanism of FXN mRNA deficiency in Friedreich’s ataxia. While there is a strong correlation between mature FXN mRNA expression and the length of the expanded GAA repeats, however, the direct mechanism of the transcriptional impairment remains unknown.

In the study, the researchers used multiple transcriptomic approaches to determine the molecular mechanism of transcription inhibition caused by long GAAs, uncovering that transcription of FXN in patient cells is prematurely terminated upstream of the expanded repeats, leading to the formation of a novel, truncated, and stable RNA.

“Mechanistically, this FXN early terminated transcript (FXN-ett) undergoes alternative, nonproductive splicing and does not contribute to the synthesis of functional frataxin,” Dr. Napierala says. “In our study, we showed that transcription progression is indeed affected at the FXN locus, resulting in the GAA-length dependent formation of an aberrant, early terminated, and alternatively spliced transcript.

“Overall, identification of a disease-enriched, early terminated transcript at FXN represents a significant step forward in understanding molecular pathology of the disease,” he explains.

THERAPEUTIC IMPLICATIONS

Importantly, the FXN transcriptional defect, FXN-ett, could be a very attractive target for therapeutic intervention.

While currently there is insufficient evidence for a direct pathogenic role of FXN-ett, formation of this stable transcript may interfere with transcription of the full-length canonical FXN pre-mRNA, thereby reducing overall transcriptional output of the FXN locus in Friedreich’s ataxia cells, Dr. Napierala explains.

“Targeting GAAs with antisense oligonucleotides or excision of the repeats eliminates the transcription impediment, diminishing expression of the aberrant FXN-ett while increasing levels of FXN mRNA and frataxin,” Dr. Napierala says. “Nonproductive transcription may represent a common phenomenon and attractive therapeutic target in diseases caused by repeat-mediated transcription aberrations.”

In light of these findings, Dr. Napierala believes a strategy of blocking nonproductive splicing of the FXN-ett RNA may lead to a natural upregulation of FXN transcription and increase of frataxin production. He and his team are conducting further experiments exploring this potential treatment approach.

ON A MISSION TO FIND A CURE

The Napierala lab, led by Dr. Napierala and Jill S. Napierala, Ph.D., an Assistant Professor of Neurology at UT Southwestern, is focused on finding a cure for Friedreich’s ataxia by elucidating molecular mechanisms causing the disease, developing novel cellular and animal models of disease, and identifying disease biomarkers, in addition to testing novel therapeutic approaches.

“The creation of our lab was a collaborative effort between the Department of Neurology and the O’Donnell Brain Institute,” Dr. Napierala says. “At the core of the mission is to foster a spirit of collaboration between our world-renowned researchers and clinicians.”

The Napierala lab takes a multidisciplinary approach to study the molecular mechanisms underlying Friedreich’s ataxia. While developing therapeutic strategies aimed at reactivating transcription of the FXN gene is a key focus for the lab, its researchers are also pioneering other projects.

“We’re also characterizing the molecular phenotypes of Friedreich’s ataxia neuronal and cardiac cells derived from induced pluripotent stem cells (iPSCs) and generating novel cellular and mouse models of disease,” he adds.

A FOCUS ON COLLABORATION, OTHER INITIATIVES

In collaboration with the Friedreich’s Ataxia Research Alliance, as well as David Lynch, M.D., Ph.D., of the Children’s Hospital of Philadelphia, the Napierala lab recently established the Friedreich’s Ataxia Cell Line Repository, which houses numerous Friedreich’s ataxia and control cell lines that are available to the research community.

The repository is the world’s largest bank of primary Friedreich’s ataxia fibroblasts and iPSCs that currently holds more than 100 lines derived from different Friedreich’s ataxia patients.

“The bank includes more than 80 disease and control fibroblast lines and 20 disease and control iPSC lines,” Dr. Napierala says. “Included in the iPSC lines are three sets of patient and isogenic, CRISPR-Cas9-edited paired lines.”

Dr. Napierala is also highly involved in the Friedreich’s ataxia patient community. The Napierala lab hosts yearly meetings with patients and their caregivers and participates in rideATAXIA events. He is also an active member of the Scientific Advisory Board of the Friedreich’s Ataxia Research Alliance.

FUTURE DIRECTIONS

Collectively, ongoing discoveries in the Department of Neurology and the O’Donnell Brain Institute may assist in the design of therapeutic strategies for ataxia and related disorders.

At OBI, researchers and clinicians work closely together, by design. Combining basic and translational research with advanced clinical care produces scientific breakthroughs that can move from the labs to patients in the clinic faster than ever.

“Within ataxia, the field is advancing rapidly – especially around novel approaches to care and curative treatments,” Dr. Shakkottai says. “From a research standpoint, there are many studies being done in this area involving our department and others across the country.”

“As discoveries continue to accelerate, we recognize that understanding the exact mechanisms of disease is essential,” Dr. Napierala says. “It is for this reason that our continued focus is on studying the molecular mechanisms of disease – uncovering the common genetic aberrations that occur across seemingly disconnected diseases.”