Simply Stated: Updates on Friedreich’s Ataxia (FRDA)

Friedreich’s ataxia (FRDA) is an inherited neuromuscular disease that primarily impacts the nervous system and heart and affects about one in 50,000 people worldwide. FRDA is characterized by a slow, progressive loss of limb coordination (ataxia) and effects on speech and swallowing.

Multidisciplinary care can improve the quality of life of people living with FRDA and research advances provide hope for therapeutic breakthroughs.

Symptoms of FRDA

People with FRDA typically begin experiencing symptoms between 5 to 15 years of age. The condition is marked by progressive ataxia, which leads to an unsteady gait when walking and poor control of fine movements of the limbs. Over time, weakness in the muscles of the mouth and throat can cause dysarthria (slow or slurred speech) and dysphagia (impaired swallowing). Muscle weakness and thinning (atrophy) often develop in the feet, lower legs, and hands. As the disease progresses, people with FRDA often require the use of a wheelchair for mobility. While most cases follow this early-onset pattern, approximately 25% of individuals with FRDA present with an “atypical” form, with late onset (early adulthood), very late onset (40 years and older), or with long-lasting retention of tendon reflexes (known as FA with retained reflexes or FARR).

FRDA is sometimes associated with complications, including diabetes mellitus (a disorder in which blood sugar levels are abnormally high), bladder and lower urinary tract symptoms, visual impairments, or hearing loss. Approximately two-thirds of individuals with FRDA develop cardiomyopathy, a disease of the heart muscles that may lead to irregularities in heart rhythm (arrhythmias) or heart failure.

For a general overview about the signs and symptoms of FRDA, read the previous post Simply Stated: What is Friedreich’s Ataxia?. For in-depth information, see the clinical review article found here.

Causes of FRDA

FRDA is caused by mutations in the FXN gene, which provides instructions for making frataxin protein. Frataxin is important for the proper functioning of mitochondria, the energy producing structures in cells. In most cases, the mutation involves an abnormal expansion of a repeated DNA sequence (GAA) within the FXN gene. This type of mutation causes reduced production of frataxin protein, disrupting mitochondrial function and impairing the health of cells. Nerve and heart cells are particularly affected because they depend on high levels of energy production from the mitochondria. FRDA is inherited in an autosomal recessive manner, meaning that two copies of the abnormal FXN gene, one from each parent, are required to cause the disease.

Current management of FRDA

Though there is currently no cure for FRDA, multidisciplinary care of affected individuals can help manage symptoms and improve quality of life. Management is based on each person’s symptoms and may include specialties such as rehabilitation medicine, occupational therapy, orthopedic intervention, speech therapy, nutrition support, cardiac and pulmonary care, and psychological care. Care recommendations developed by physician and scientist experts in FRDA (Corben, et al, 2014 and Friedrich’s Ataxia Research Alliance) are available to guide physicians in evidence-based treatment of people living with FRDA.

In addition to symptom management, new therapeutics offer hope for people living with FRDA. On Feb. 28, 2023, the US Food and Drug Administration (FDA) approved omaveloxolone (SKYCLARYS™) (Reata Pharmaceuticals) for the treatment of FRDA in adults and adolescents aged 16 years and older. Skyclarys is a small molecule drug that activates the Nrf2 transcription factor, and is thought to trigger a cellular response that helps reduce inflammation and restore mitochondrial function in individuals with FRDA.

Evolving research and treatment landscape

While the standard of care for FRDA is still symptom management, research advances and the promise of better therapeutics on the horizon offer hope for people living with the disease.

Researchers are currently investigating therapeutic strategies that may reverse some of the abnormal processes that occur within the cells of people with FRDA. In FRDA, reduced levels of frataxin disrupt normal mitochondrial function, leading to iron buildup and the excessive production of free radicals that cause oxidative stress and cellular damage, particularly in the nervous system and heart. Therapies to improve mitochondrial function and reduce oxidative stress have shown promise in clinical trials. Also under active investigation are methods to increase frataxin levels and gene replacement therapy approaches to correct the underlying defect in FRDA.

Several promising therapies are being studied in clinical trials that are actively enrolling participants. While the following is not a comprehensive list, it highlights select opportunities for individuals who may be interested in contributing to ongoing research.

Interventional trials

Frataxin replacement and gene therapies

Nomlabofusp (CTI‑1601) (Larimar Therapeutics) – This therapy works by delivering a functional, human frataxin protein to the mitochondria in cells. A phase 2 study to determine the optimal dose in adults with FRDA was completed in 2023, with an open label extension currently enrolling by invitation. The therapy is also being studied in a phase 1/2 clinical trial in children ages 2-17 years old with FRDA.

LX2006 (AAVrh.10‑hFXN) (Weill Medical College of Cornell University and Lexeo Therapeutics) – This therapy uses an adeno-associated virus (AAV) gene therapy vector to deliver a normal copy of the FXN gene into heart muscle cells. It is being studied in both a phase 1 trial sponsored by Weill Medical College of Cornell University and a phase 1/2 (SUNRISE-FA) trial sponsored by Lexeo Therapeutics in adults with cardiac symptoms related to FRDA.

Frataxin expression enhancers

DT‑216 (Design Therapeutics) – This therapy is a small molecule that targets GAA repeat expansions in the FXN gene, helping to restore normal gene expression and increase frataxin protein production. It is being studied in a phase 1 clinical trial in adults with FRDA. Investigators are evaluating the safety and biological effects of increasing dose levels.

Oxidative Stress and Neuroprotection Modulators

Vatiquinone (PTC Therapeutics) – This is a small molecule therapy that is taken orally (by mouth). It is designed to target an enzyme (15-lipoxygenase) that regulates inflammation, oxidative stress and death pathways in the cell. The long-term effect of vatiquinone in people with FRDA is being studied in an open-label phase 3 trial that is active, but not recruiting participants. The therapy is also currently under review by the FDA with a PDUFA date (goal date for approving or denying the drug for marketing) of August 19, 2025.

Natural history studies

In addition to interventional trials, several natural history studies are actively enrolling participants with FRDA. These studies are not testing treatments directly, but will provide crucial clinical data and infrastructure to support future interventional trials for FRDA. Natural history studies currently enrolling in the United States include, though are not limited to, the following:

Biomarkers in FA (University of Florida) – This study is characterizing cardiac and neurological measures using MRI, metabolic testing, and neurophysiology. People with FRDA from ages 8–70 years old are being recruited for this study.

UNIFIED Natural History Study (Friedreich’s Ataxia Research Alliance) – This is a global longitudinal (over time) study open to people with FRDA. The goal is to collect data that will help to understand disease progression and support the development of safe and effective drugs and biological products for FRDA.

To learn more about clinical trial opportunities in FRDA, visit clinicaltrials.gov and search for “Friedreich’s ataxia” in the condition or disease field.

MDA’s work to further cutting-edge FRDA research

Over the past two years, MDA has proudly partnered with the Friedreich’s Ataxia Research Alliance (FARA) to co-fund two research grants aimed at advancing therapeutic discovery for FRDA:

• Jonathan Watts, University of Massachusetts Chan Medical School – Paired Prime Editors to treat Friedreich’s ataxia (2024). In this project, Watts and team are developing a gene editing approach called prime editing to precisely remove the GAA repeat expansion that causes FRDA, aiming to correct the FXN gene at it source. They are testing and comparing several versions of the technology to identify the most efficient and safest strategy for targeting the gene with minimal off-target effects.
• Giovanni Manfredi, Weill Medical College of Cornell University – Molecular and cellular mechanisms of cardiac fibrosis in Friedreich’s ataxia (2025). This project aims to better understand how heart damage develops in FRDA, focusing on the role of fibrosis, or scarring, that stiffens the heart and contributes to the heart failure and arrhythmias. Using mouse models, the researchers are studying the specific cell types and molecular pathways that drive this scarring process, with the goal of identifying new therapeutic targets to protect the heart in people with FRDA.

Through its Venture Philanthropy program (MVP), MDA previously provided funding to AavantiBio, a biotechnology company developing an AAV-based gene therapy to correct the underlying genetic defect in FRDA. In 2022, AavantiBio was acquired by Solid Biosciences, which is now advancing its lead candidate, SGT-212, a gene therapy designed to address both the neurological and cardiac symptoms of FRDA. SGT-212 received FDA Fast Track designation earlier this year, a status intended to accelerate its development and review in order to address the unmet medical needs of individuals living with FRDA.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about Friedreich’s ataxia, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.