Objective: To identify genetic disease and efficacy markers for Friedreich’s ataxia (FRDA)

Background: FRDA is a genetic disease caused by decreased expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive cardiac and neuronal degeneration. It affects about 5,000 people in the United States and 20,000 in Europe and is the most common form of hereditary ataxia. Presently, there is no approved treatment for FRDA, and no molecular biomarkers have been identified to monitor disease progression and evaluate the activity of therapeutic approaches. FXN plays a major role in the activity of many enzymatic reactions involving electron transfer, and therefore is an important contributor to mitochondrial homeostasis. Bidirectional signaling between mitochondria and the nucleus has been documented in numerous organisms through which cellular homeostatic or proteostatic changes trigger changes of gene expression from both the nuclear and mitochondrial genomes. Accordingly, we and others have reported that variation of FXN levels impacts the expression of several genes.

Method: Using several experimental models of FXN reduction, and our experimental drug CTI-1601 that repletes FXN levels, we defined a set of FXN-sensitive gene markers (FSGMs). Buccal and blood cells were collected at similar timepoints from either healthy individuals or FRDA patients treated with CTI-1601 or placebo in a double-blind, multiple ascending dose safety study. RNA was purified and absolute gene expression levels were measured using Nanostring® technology. Data were normalized and relative gene expression for all FSGMs established.

Results: We identified over 20 genes that, in buccal cells, are differentially expressed between patients and healthy individuals in a statistically significant manner (p_adj<0.05). Interestingly, some of those genes are major regulators of the mitochondrial oxidative stress response, mitophagy, and neuron development and survival. Remarkably, treatment with CTI-1601 significantly reversed the expression levels of 6 of those genes to levels observed in healthy individuals.

Conclusion: Quantitation of expression levels of a small number of genes in buccal cells can be used to discriminate between healthy individuals and patients with FRDA. Treatment with CTI-1601 is effective in restoring the expression levels of 6 of those genes to levels similar to those observed in healthy individuals.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-expression-quantification-to-assess-frataxin-replacement-therapies-in-friedreichs-ataxia/