Preclinical efficacy of targeting enzymes for Friedreich’s ataxia treatment

Friedreich’s ataxia (FRDA) is a rare, inherited neurodegenerative disorder with limited treatment options. Our project explores the novel role of sphingolipid metabolism in FRDA, a pathway linked to other neurodegenerative diseases but not yet studied in this context. By identifying key regulators and therapeutic targets, we aim to uncover new mechanisms and develop strategies to improve outcomes for individuals affected by this devastating condition.

Our project aims to explore the role of sphingolipid metabolism in FRDA. By identifying key regulatory pathways and novel drug targets, our research has the potential to pave the way for more comprehensive and effective therapies. Beyond addressing a critical medical need, this work contributes to broader societal goals by advancing scientific knowledge, supporting the development of treatments for rare childhood diseases, and improving the quality of life and life expectancy for affected individuals and their families.

While most FRDA research has focused on mitochondrial dysfunction and oxidative stress, our project takes a novel approach by investigating the role of sphingolipid metabolism, a pathway increasingly linked to neurodegeneration but largely unexplored in FRDA. By focusing on key regulatory enzymes and genes involved in sphingolipid metabolism, we aim to pinpoint novel therapeutic targets.

Friedreich’s ataxia (FRDA) is a rare, inherited neurodegenerative disorder and the most common form of childhood-onset ataxia, affecting approximately 1 in 50,000 individuals of Caucasian descent. FRDA typically presents in early childhood with progressive difficulty walking due to impaired coordination, known as ataxia. As the disease advances, individuals often develop severe musculoskeletal deformities and lose mobility. Most patients succumb to heart failure or related complications in early adulthood.

FRDA is caused by a mutation in the FXN gene, which encodes frataxin, a protein essential for mitochondrial function. Frataxin deficiency disrupts iron homeostasis within mitochondria, leading to the accumulation of toxic byproducts, increased oxidative stress, and ultimately cellular death.

Currently, Omaveloxolone (SKYCLARYS™) is the only approved treatment for FRDA in the USA and EU. While it provides neurological benefits, its effects on other clinical aspects of the disease remain to be fully understood. This underscores the need to identify additional therapeutic targets that could broaden treatment strategies for FRDA.

Emerging evidence suggests that defective sphingolipid metabolism may contribute to the pathology of various neurodegenerative diseases, including childhood-onset conditions such as Tuberous Sclerosis Complex and Fatty Acid Hydroxylase-associated Neurodegeneration, as well as adult-onset diseases like Alzheimer’s, Huntington’s, and Parkinson’s. Sphingolipids are a class of lipids vital to brain function, and disturbances in their metabolism can have significant neurological consequences.

Our recent findings indicate altered sphingolipid levels and dysregulation of associated genes in both mouse models and human samples of FRDA. These changes may play a crucial role in disease progression. The goal of this project is to investigate key regulators of sphingolipid metabolism in FRDA and to identify novel therapeutic targets.