RARE DISEASE
Friedreich ataxia
Friedreich ataxia
Friedreich ataxia
Synonyms: FA, FRDA
Synonyms: FA, FRDA
Synonyms: FA, FRDA
Drug discovery
36
drugs
With orphan designations
Overview
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency. It features progressive ataxia, dysarthria, sensory loss, hypertrophic cardiomyopathy (60–75% of cases), scoliosis, and diabetes (20–30%). Onset typically occurs in childhood/adolescence, with wheelchair dependence within 10–20 years. Multisystem involvement necessitates multidisciplinary care. Mortality averages 36–37 years, often due to cardiac complications [1][6][14][16].
Burden
Morbidity: 95% require wheelchairs by age 45; 32% non-ambulatory by adulthood [4][14].
Mortality: Median age of death 36.5 years; cardiac complications (62%) are the leading cause [2][5][14].
Economic impact: Annual US healthcare costs exceed $18,000/patient (adjusted), with 6x higher home health needs vs. controls [4][5][14].
Therapies
Symptomatic management: Physical/occupational therapy, botulinum toxin for spasticity, beta-blockers/ACE inhibitors for cardiomyopathy [3][6][15].
Disease-modifying: Omaveloxolone (Skyclarys®), the first FDA-approved therapy, reduces oxidative stress and slows progression [8][17].
Emerging approaches: Gene therapy, frataxin replacement, and epigenetic modifiers in clinical trials [13][18][19].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
1,045 drug discovery papers about Friedreich ataxia, with 4 first-in-class and 26 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,045 drug discovery papers about Friedreich ataxia, with 4 first-in-class and 26 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-04 | Omaveloxolone-Associated Lipid Changes in Friedreich Ataxia: Mechanistic Inference, Concomitant Therapy, and Regulatory Terminology
Recent real-world data from 17 patients with Friedreich ataxia treated with omaveloxolone showed sustained increases in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), while very-low-density lipoprotein cholesterol (VLDL-C) and triglyceride concentrations remained stable. Buchinger et al. interpreted this pattern as favouring impaired clearance of ApoB-containing particles over increased hepatic lipoprotein production. This commentary examines the limits of that inference. Circulating lipid concentrations reflect the net effects of production or secretion, intravascular remodelling and interconversion, and clearance; human stable-isotope studies illustrate that offsetting kinetic changes can leave circulating concentrations unchanged. Reduced LDL receptor function may also be accompanied by altered production as well as clearance, although this does not establish an analogous mechanism for omaveloxolone. Two additional issues merit consideration: concomitant lipid-lowering therapy, including the possibility of reduced rosuvastatin exposure, and the description of several eligibility thresholds as approved contraindications. The LDL-C and ApoB increases remain clinically relevant, but their underlying mechanism remains unresolved; concomitant therapy may influence individual trajectories, and the regulatory terminology warrants correction.
2026-08-27 | Could NQO1 genotypes impact the results of clinical trials with idebenone?
Carelli et al. argue that new insights into how NQO1 influences the response to idebenone warrant reevaluating the results of previous clinical trials, including those in Friedreich ataxia and Duchenne muscular dystrophy, using patient stratification by NQO1 genotype.
2026-08-06 | BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.
How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich's ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression.
2026-07-30 | Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich's ataxia.
Friedreich ataxia (FRDA) is a neurodegenerative and cardiac disease caused by GAA repeat expansions within the first intron of the FXN gene, leading to reduced frataxin expression. Frataxin is involved in iron sulfur cluster (ISC) biosynthesis, and its deficiency results in multiple cellular dysfunctions, including mitochondrial iron overload. Although altered iron homeostasis has been reported in several frataxin-deficient models and in FRDA patients, its contribution to disease progression remains debated. Here, we used a GAA expansion-based Drosophila model of FRDA, termed fh-GAAs, to investigate the impact of reducing intestinal iron absorption on disease progression. We first found that iron accumulation was tissue-specific and predominantly affected the central nervous system. Furthermore, glial cells were affected more severely than neurons, suggesting an increased vulnerability of glia to frataxin deficiency. Reducing intestinal iron uptake, either through treatment with bathophenanthroline disulfonic acid (BPS), an extracellular iron chelator, or by gut-specific silencing of the gene encoding the iron transporter Malvolio, nearly doubled fly survival. BPS treatment also improved sensitivity to dietary iron, enhanced locomotor performance, fully restored normal brain size, and prevented glial alterations. Altogether, our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the in vivo relevance of intestinal iron uptake as a potential modulator of disease severity in FRDA.
2026-07-28 | Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis.
Background: Friedreich's ataxia (FRDA) is a neurodegenerative disorder driven by frataxin deficiency, resulting in mitochondrial dysfunction and reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Pharmacologic trials have yielded inconsistent results, prompting an updated synthesis of evidence. Methods: We searched MEDLINE/PubMed, Google Scholar, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) from database inception to 29 June 2025. Embase, Scopus and Web of Science were not searched due to institutional access limitations. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Random-effects meta-analyses were conducted, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used. Primary outcomes were modified Friedreich Ataxia Rating Scale (mFARS)/Friedreich Ataxia Rating Scale (FARS); safety outcomes included adverse events (AEs) and serious AEs. Secondary outcomes were Scale for the Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS), Nine-Hole Peg Test, and the Timed 25-Foot Walk. Results: Sixteen studies (17 reports, n = 351) met inclusion criteria. Omaveloxolone was the only agent showing a statistically significant improvement in mFARS (mean difference (MD) -2.40; 95% confidence interval (CI) -4.24 to -0.56; p = 0.014), supported by low-certainty evidence. Other therapies showed no consistent benefit. Overall AE risk was comparable to control (risk ratio (RR) 1.00; 95% CI 0.98-1.03). Apparent subgroup differences by therapeutic class or age likely reflected drug-specific effects and small samples. Conclusions: Omaveloxolone was the only agent to reach statistical significance for mFARS and is the most promising and best-supported therapy among those reviewed; however, this rests on low-certainty evidence and needs confirmation in larger trials. No clear difference in overall adverse events was observed between intervention and control groups; however, available safety evidence remains limited by imprecision, small sample sizes, and short follow-up durations. Longer, standardized, and age-stratified randomized controlled trials (RCTs) are needed.
oligonucleotides
2025-12-11 | Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.
2025-10-15 | Targeting rare splicing defects: Antisense oligonucleotides offer a therapeutic strategy in FRDA
Friedreich’s ataxia (FRDA) is an autosomal recessive, multisystem disorder caused by mutations in the FXN gene, progressively affecting the nervous system, heart, and other organs.1 A recent study published in Molecular Therapy Nucleic Acids by Yameogo et al. describes a novel, intronic point mutation that disrupts canonical splicing and severely reduces FXN mRNA and frataxin protein levels.2 Using patient-derived cells, the authors demonstrated that antisense oligonucleotides (ASOs) targeting splicing regulatory elements effectively restore splicing deficits and increase frataxin expression.
2025-07-24 | Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.
Friedreich's ataxia (FRDA) is a multisystem, progressive disease. 96% of patients carry biallelic GAA triplet expansion mutations in intron 1 of the frataxin gene (FXN). The remaining 4% have a pathogenic GAA expansion on one FXN allele and another mutation on the second allele. A point mutation, FXN c.165+5G>C, was identified in intron 1 of a patient with FRDA resulting in a significant decrease of FXN levels. Using patient fibroblasts, we demonstrated that the c.165+5G>C mutation affects canonical splicing of FXN, leading to the generation of an aberrant transcript. A library of antisense oligonucleotides (ASOs) was designed to target potential intronic splicing regulator motifs and tested in patient cells. Selected O-methoxyethyl (MOE)-ASOs increased FXN levels in c.165+5G>C patient cells without affecting FXN splicing in control cells. The leading MOE-ASO increased expression of a miniFXN gene carrying the c.165+5G>C point mutation by splicing repair. To increase efficacy, we simultaneously targeted the GAA-expanded allele in patient cells using a synthetic transcription factor (synthetic transcription elongation factor 1 [Syn-TEF1]). This ASO strategy may be therapeutically feasible for patients with FRDA with other point mutations that cause splicing defects. Success in developing treatments for disorders with only a few known cases will give hope to patients with FRDA carrying these rare point mutations.
2025-06-09 | Anti-gene oligonucleotides targeting Friedreich's ataxia expanded GAA⋅TTC repeats increase Frataxin expression.
Friedreich's ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA⋅TTC triplet-repeats in the first intron of the Frataxin gene. GAA⋅TTC repeat expansion results in the formation of a non-B-DNA intramolecular triplex as well as changes in the epigenetic landscape at the Frataxin locus. Expansion of intronic GAA⋅TTC repeats is associated with reduced levels of Frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA⋅TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in Frataxin mRNA and protein levels in cells derived from Friedreich's ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA⋅TTC DNA repeats to upregulate Frataxin gene expression.
2025-03-23 | Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases.
Neurodegenerative diseases (NDD) are characterized by the progressive loss of neurons and the impairment of cellular functions. Messenger RNA (mRNA) has emerged as a promising therapy for treating NDD, as it can encode missing or dysfunctional proteins and anti-inflammatory cytokines or neuroprotective proteins to halt the progression of these diseases. However, effective mRNA delivery to the central nervous system (CNS) remains a significant challenge due to the limited penetration of the blood-brain barrier (BBB). Lipid nanoparticles (LNPs) offer an efficient solution by encapsulating and protecting mRNA, facilitating transfection and intracellular delivery. This review discusses the pathophysiological mechanisms of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), ischemic stroke, spinal cord injury, and Friedreich's ataxia. Additionally, it explores the potential of LNP-mediated mRNA delivery as a therapeutic strategy for these diseases. Various approaches to overcoming BBB-related challenges and enhancing the delivery and efficacy of mRNA-LNPs are discussed, including non-invasive methods with strong potential for clinical translation. With advancements in artificial intelligence (AI)-guided mRNA and LNP design, targeted delivery, gene editing, and CAR-T cell therapy, mRNA-LNPs could significantly transform the treatment landscape for NDD, paving the way for future clinical applications.
cell therapies
2026-09-15 | Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
2026-01-23 | Zygomatic Screws for Severe Open Bite Closure in a Young Friedreich's Ataxia Patient: A Case Report.
Friedreich's ataxia is an inherited disease affecting the nervous system and presents huge orthodontic challenges affecting the patient's coordination and muscular function. Based on the rarity of this condition, the aim of this case report is to describe an unusual orthodontic treatment employed to manage a severe open bite in a 14-year-old male patient suffering from Friedreich's ataxia, by highlighting the clinical decisions and treatment outcomes. Managing a severe anterior open bite in patients suffering from Friedreich's ataxia by skeletal anchorage mechanics for posterior teeth intrusion is advantageous considering their health condition.
2026-01-10 | Human pluripotent stem cell models of Friedreich's ataxia: innovations, considerations, and future perspectives.
Friedreich's ataxia (FRDA) is an inherited, autosomal recessive, multisystem disorder that primarily manifests in children and affects the nervous system and the heart. FRDA is caused by an expansion of GAA repeats in the first intron of the frataxin (FXN) gene. The expansion disrupts transcription of FXN, resulting in significantly decreased FXN expression in FRDA patients' tissues. Frataxin is involved in biosynthesis of iron-sulfur (Fe-S) clusters, which are critical for the function of the electron transport chain and many metabolic enzymes. Frataxin deficiency leads to reduced energy production and accumulation of iron in mitochondria that exacerbates oxidative stress. Despite significant advancements in the field, FXN cellular functions and underlying pathological mechanisms of FXN deficiency in cell-type specific contexts remain to be elucidated. Inaccessibility to the most vulnerable cell types in FRDA patients, including neurons, cardiomyocytes, and β-cells, largely accounts for these limitations. Significant progress in recent years regarding the derivation and differentiation of human pluripotent stem cells (hPSCs), along with breakthroughs in gene editing technologies, enables the generation of patient-derived and isogenic control disease-relevant cell types and organoid-like structures as platforms for studying disease mechanisms and for drug discovery. Herein, we first provide an overview of hPSC derivation and intrinsic properties of these cells. We then discuss current advances and limitations of hiPSC-based cell models for FRDA. We also highlight the need to further refine and develop these in vitro cell models for pre-clinical advancement of therapeutic approaches for FRDA.
2025-12-19 | Respiratory Function in Friedreich's Ataxia.
Friedreich's ataxia (FA) is a neurodegenerative disorder often accompanied by respiratory dysfunction, but detailed respiratory profiles remain understudied. To evaluate pulmonary parameters and respiratory muscle strength in individuals with FA compared with healthy controls. Sixteen FA patients and 20 age-matched healthy controls underwent spirometry, maximal inspiratory and expiratory pressure measurements, sniff nasal inspiratory pressure (SNIP), phrenic nerve conduction study, peripheral oxygen saturation (SpO2), and end-tidal CO2 (ETCO2). Respiratory parameters were analyzed using Student's t-test or Mann-Whitney test, and linear or quantile regression adjusted for body mass index and smoking status. Ataxia severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). FA patients exhibited significantly reduced forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), alongside decreased maximal respiratory pressures (P < 0.01). A restrictive ventilatory pattern predominated. Peripheral oxygen saturation was lower in the FA group (P < 0.01). Respiratory impairment appears mostly subclinical, suggesting that FA patients may be vulnerable to pulmonary infections and ventilatory failure. This dysfunction may reflect both neuromuscular weakness and impaired respiratory coordination. Early and regular respiratory assessment, together with preventive and rehabilitative strategies integrated into multidisciplinary care, may improve quality of life and potentially prolong survival in individuals with FA. © 2025 International Parkinson and Movement Disorder Society.
2025-02-11 | Myeloid Cell Replacement Therapy Improves Function in Friedreich Ataxia Mice by Intercellular Mitochondrial Transfer
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency, leading to neurodegeneration and cardiomyopathy. Currently, there are no effective therapies for FA. Our study investigated the potential of myeloid cell replacement using bone marrow-derived cells in the YG8-800 mouse model. Combining Busulfan myeloablation, Colony-stimulating factor 1 receptor inhibition, and bone marrow transplantation, we achieved almost complete microglia and tissue macrophage replacement. This replacement facilitated mitochondrial transfer to various CNS cells, enhancing ATP synthesis and oxidative phosphorylation and improving the mice's growth and neurobehavioral performance. Similarly, replacing macrophages restored function and increased mitochondrial activity in the heart. In vitro studies showed that transferring intact mitochondria partially restored respiratory capacity in FA cells, which had a higher uptake, suggesting a specific compensatory mechanism for mitochondrial acquisition. These findings suggest that myeloid cell replacement can promote metabolic recovery in FA through mitochondrial transfer and provide a new approach to treating FA and other mitochondrial disorders.
gene therapies
2026-09-01 | TwinPE delivered as RNA or VLP enables precise deletion of GAA repeats in the FXN gene
Friedreich’s ataxia (FRDA or FA) is a rare autosomal recessive neurodegenerative disorder caused by guanine-adenine-adenine (GAA) repeat expansions in the first intron of the frataxin ( FXN ) gene. To address this underlying genetic cause, we developed paired prime editors (twinPE) to precisely delete GAA repeats. Using a 38-bp attachment site of bacteria ( attB ) sequence as the reverse transcription template (RTT), we achieved a precise 1.2-kb deletion with attB insertion in HEK293T cells with a 48.0% editing efficiency. We further delivered two synthetic pegRNAs and PE6 mRNA into GM03816 FRDA fibroblasts and GM23404, as well as GM23913 patient-derived induced pluripotent stem cells (iPSCs) via electroporation, achieving average editing rates of 13.3%, 40.6%, and 25.0%, respectively. In both patient-derived iPSCs, twinPE successfully restored FXN expression, resulting in a ∼2-fold increase in mRNA levels, relative to non-treated controls, demonstrating a promising functional correction of gene expression. Importantly, NGS analysis revealed that >95% of all edits were precise, with minimal indels across all tested cell types. We directly delivered twinPE to iPSC-derived motor neurons (iMNs) using virus-like particles (VLPs), achieving 12.6% editing. In summary, our results demonstrate that twinPE enables efficient and precise deletion of GAA repeats across multiple cell types, including iMNs. The restoration of FXN mRNA in iPSCs represents a promising functional recovery, establishing a foundation for twinPE-mediated genome editing as a potential therapeutic strategy for FRDA.
2026-07-13 | CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives.
Huntington's disease (HD) and Friedreich's ataxia (FRDA) are progressive inherited neurodegenerative disorders caused by trinucleotide repeat expansions but characterized by distinct pathogenic mechanisms. HD arises from a coding-region CAG expansion in the HTT gene that produces toxic gain-of-function effects of mutant huntingtin (mHTT), whereas FRDA results primarily from intronic GAA repeat expansion in FXN, leading to epigenetic repression and frataxin deficiency. The emergence of CRISPR-based genome engineering has created new opportunities to address these diseases at their genetic origin. This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.
2026-04-15 | From Genetic Mutation to Therapy in Friedreich Ataxia: Molecular Mechanisms, Therapeutic Advances, and Translational Challenges
Friedreich ataxia (FRDA) is a rare, autosomal recessive, progressive neurodegenerative disorder characterized by multisystem involvement, including gait and limb ataxia, cardiomyopathy, skeletal deformities, and metabolic dysfunction. Most patients harbor biallelic GAA trinucleotide repeat expansions in intron 1 of FXN, whereas others are compound heterozygotes with a GAA expansion on one allele and a pathogenic FXN variant on the other. FXN encodes frataxin, a nuclear-encoded mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis and mitochondrial energy production. Frataxin deficiency disrupts mitochondrial metabolism, promotes iron dysregulation and oxidative stress, and leads to progressive cellular injury, particularly in high-energy tissues such as the nervous system and myocardium. Despite substantial advances in understanding FRDA pathogenesis, no curative therapy is currently available. In 2023, omaveloxolone (Skyclarys) became the first approved treatment for FRDA, marking a significant therapeutic milestone. Concurrently, disease-directed strategies have expanded rapidly, including small-molecule modulators, adeno-associated virus (AAV)-mediated gene replacement, and transcriptional or epigenetic approaches aimed at restoring endogenous FXN expression. In addition, antisense oligonucleotide-based therapies and emerging CRISPR-mediated gene editing platforms are advancing through preclinical and early clinical development. This review provides a comprehensive overview of the evolving therapeutic landscape in FRDA, highlighting mechanistic rationales, preclinical progress, clinical trial outcomes, and the key translational challenges that must be addressed to achieve durable disease modification.
2026-01-28 | Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review.
Neurodevelopmental disorders (NDDs) with ataxia are genetically heterogeneous and remain a diagnostic challenge. Recent advances in genomic technologies have facilitated the identification of rare, potentially causative variants in genes not traditionally associated with classic NDD phenotypes. The DNAH14 gene, encoding a dynein axonemal heavy chain involved in ciliary motility, has recently emerged as a novel candidate in neurological syndromes. Here, we report two Turkish siblings presenting with late-onset balance disorder, progressive ataxia, and cognitive impairment. Initial genetic analysis revealed that both siblings also harbor FXN GAA repeat expansions consistent with pathogenic Friedreich's ataxia (FRDA). To elucidate the molecular basis of the patients' cognitive impairment, whole-exome sequencing was performed. This analysis identified a novel homozygous frameshift variant in the DNAH14 gene, located within the conserved linker domain upstream of the motor core, which is critical for ATP hydrolysis and microtubule interactions. The variant is absent from population databases, predicted to be deleterious by multiple in silico algorithms, and segregates in the family in a manner consistent with autosomal recessive inheritance. The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.
2025-11-30 | Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.
other
2026-09-08 | Mitochondrial Quality Control as the Mechanistic Hinge of Inherited Cardiomyopathy: Convergent Pathobiology and Targeted Therapy
Inherited mitochondrial cardiomyopathies arise from pathogenic variants that disrupt oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin biogenesis, or mitochondrial dynamics and quality control. Although the causative genes are diverse—mtDNA mutations, nuclear respiratory-chain and assembly factors, TAZ in Barth syndrome, FXN in Friedreich ataxia, AGK in Sengers syndrome—the resulting cardiac disease converges on a shared endpoint: bioenergetic insufficiency with cristae destabilization, calcium mishandling, redox imbalance, and failure of mitophagy-dependent quality control. We synthesize how these distinct lesions funnel into common pathways of hypertrophy, fibrosis, and arrhythmogenesis, and argue that this convergence, rather than any single gene, defines the actionable therapeutic space. Mapping treatment onto these nodes, we discuss cardiolipin-directed stabilization with elamipretide—approved for Barth syndrome in 2025—gene-replacement and editing strategies (AAV-delivered TAZ and FXN, mitochondrial base editing), and cofactor, substrate-bypass, and mitophagy-modulating approaches. We propose a falsifiable central hypothesis with testable predictions, and confront the field’s principal obstacles: genetic heterogeneity requiring patient stratification, an apparent fibrotic ceiling on reversibility, and mitochondrial delivery barriers. Positioning mitochondrial quality control as the mechanistic hinge, we outline a stratified, mechanism-guided route toward cardiac-specific therapy.
2026-08-10 | Impaired Glur2 palmitoylation in cerebellar Purkinje cells of a Friedreich ataxia mouse model.
Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by frataxin deficiency, characterized by progressive cerebellar dysfunction and neuronal loss. Although synaptic abnormalities are an early feature of FRDA, the molecular mechanisms linking frataxin deficiency to synaptic dysfunction remain incompletely defined. In this study, we investigated post-translational regulation of the AMPA receptor subunit GluR2 in the cerebellum of the frataxin knockdown (FRDAkd) mouse model. GluR2 protein levels are reduced early following frataxin knockdown, despite unchanged mRNA expression and preserved Purkinje cell number. Phosphorylation of GluR2 at regulatory sites (Ser880 and Tyr876) is unchanged relative to total protein, indicating that altered phosphorylation does not account for reduced GluR2 levels. In contrast, acyl-biotin exchange assays and proximity ligation analysis reveal a significant reduction in GluR2 palmitoylation, localized primarily to Purkinje cell somata. This deficit is selective, as palmitoylation of other synaptic proteins is variably affected. Mechanistically, reduced GluR2 palmitoylation associates with decreased expression and palmitoylation of the palmitoyl acyltransferase DHHC3, while levels of depalmitoylating enzymes remain unchanged. In vitro, DHHC3 enhances GluR2 palmitoylation, supporting a direct enzymatic relationship. Partial restoration of frataxin expression rescues GluR2 and DHHC3 protein levels and partially restores GluR2 palmitoylation. These findings identify impaired GluR2 palmitoylation as an early, selective synaptic alteration in FRDA and implicate dysregulated lipid-dependent post-translational modification as a mechanism linking frataxin deficiency to cerebellar synaptic vulnerability.
2026-06-17 | Genetic modifiers of Friedreich's ataxia pathophysiology in Drosophila melanogaster - A systematic review and meta-analysis.
Friedreich's ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by reduced frataxin protein levels. Depleted frataxin leads to mitochondrial dysfunction, elevated oxidative stress and progressive neurodegeneration. The molecular mechanisms that regulate the severity of disease are still poorly understood. Genetic modifiers have proved to be important determinants of the disease pathophysiology and in uncovering novel therapeutic targets. This systematic review and meta-analysis was conducted to compare the effectiveness of different genetic modifiers of the pathophysiology of the FRDA in Drosophila model. Articles were screened as per PICO criteria and included articles were assessed for methodological quality using SYRCLE tool and plotted using robvis tool. Genetic modifiers improved survival (effect size (ES) 0.2082), brain vacuolization, Electroretinogram (ERG) (ES 0.6373), locomotion (ES 0.3356), and aconitase activity (ES 0.2087), of Drosophila FRDA models while the heterogeneity was high across different studies for all phenotypes. Genetic modifiers were compared on the basis of efficacy, reproducibility, mechanistic relevance, safety, therapeutic plausibility and graded for their effectiveness on disease pathogenicity. Ferritins overexpression, Miro inhibition, and catalase overexpression, converging pathways iron homeostasis, mitochondrial dynamics and oxidative stress management, were found to be the top ranked modifiers for their beneficial effects on FRDA pathophysiology and were suggested for further studies as therapeutic targets. Based on the limitations identified in this systematic review and meta-analysis, we recommend that subsequent research studies adopt standardized reporting practices, multiple phenotype validation, supporting behavioural outcomes with biochemical and cellular readouts, using genetically precise models and systematic sharing of raw data to enhance reproducibility and research value.
2026-05-19 | Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
Recent discoveries reveal that frataxin (FXN) and ferredoxin 2 (FDX2) competitively regulate mitochondrial iron-sulfur (Fe-S) cluster biosynthesis through their binding to the cysteine desulfurase NFS1 and the iron-sulfur cluster scaffold protein ISCU2 complex. Here, we discuss the potential of rationally designed peptide inhibitors targeting the FDX2-NFS1 interaction as a strategy to mitigate FXN deficiency and restore Fe-S cluster biosynthesis.
2026-01-21 | Integration of Evolutionary Analysis With RFdiffusion for De Novo Design of Aggregation-Resistant Frataxin.
Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by frataxin (FXN) deficiency, where protein replacement therapy is hampered by the inherent instability and aggregation propensity of wild-type (WT) FXN. The structural flexibility of Loop-1 (residues 115-123), a critical region within the acidic ridge, represents a key determinant of protein stability. This study introduces a computational pipeline integrating evolutionary conservation analysis (ConSurf) with diffusion-based de novo design (RFdiffusion) to redesign both the backbone and sequence of Loop-1. Through systematic filtration of 1000 ProteinMPNN-generated variants using aggregation propensity screening (AGGRESCAN) and 450 ns of molecular dynamics (MD) simulations, four lead candidates were identified. Design_188 (EERVGGREI) demonstrated optimal performance with 2.3-fold improvement in aggregation resistance (Na4vSS: -53.8 vs. -23.5 for WT), superior structural stability (RMSD: 0.486 nm), reduced conformational diversity (62.3% dominant cluster occupancy), and 93% retention of ISCU binding capacity (ΔΔG: +6.4 kcal/mol). Experimental validation through 15N NMR relaxation analysis confirmed computational predictions, with Design_188 exhibiting uniform backbone rigidification (S2 = 0.81-0.95) and strong MD-NMR correlation (Pearson r = 0.675, p = 0.003). SEC-MALS analysis demonstrated near-complete monomeric behavior (> 98% monomer content) compared to WT's heterogeneous oligomerization (68% monomer, 32% oligomers), directly confirming the predicted anti-aggregation properties. K-means clustering analysis revealed an inverse relationship between conformational heterogeneity and stability, while correlation analysis identified a fundamental trade-off between aggregation resistance and structural stability (r = -0.82, p < 0.01). This work establishes a generalizable framework for therapeutic protein engineering where backbone redesign enables conformational ensemble modulation beyond the limitations of sequence optimization alone.
small molecules
2026-09-04 | Omaveloxolone-Associated Lipid Changes in Friedreich Ataxia: Mechanistic Inference, Concomitant Therapy, and Regulatory Terminology
Recent real-world data from 17 patients with Friedreich ataxia treated with omaveloxolone showed sustained increases in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), while very-low-density lipoprotein cholesterol (VLDL-C) and triglyceride concentrations remained stable. Buchinger et al. interpreted this pattern as favouring impaired clearance of ApoB-containing particles over increased hepatic lipoprotein production. This commentary examines the limits of that inference. Circulating lipid concentrations reflect the net effects of production or secretion, intravascular remodelling and interconversion, and clearance; human stable-isotope studies illustrate that offsetting kinetic changes can leave circulating concentrations unchanged. Reduced LDL receptor function may also be accompanied by altered production as well as clearance, although this does not establish an analogous mechanism for omaveloxolone. Two additional issues merit consideration: concomitant lipid-lowering therapy, including the possibility of reduced rosuvastatin exposure, and the description of several eligibility thresholds as approved contraindications. The LDL-C and ApoB increases remain clinically relevant, but their underlying mechanism remains unresolved; concomitant therapy may influence individual trajectories, and the regulatory terminology warrants correction.
2026-08-27 | Could NQO1 genotypes impact the results of clinical trials with idebenone?
Carelli et al. argue that new insights into how NQO1 influences the response to idebenone warrant reevaluating the results of previous clinical trials, including those in Friedreich ataxia and Duchenne muscular dystrophy, using patient stratification by NQO1 genotype.
2026-08-06 | BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.
How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich's ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression.
2026-07-30 | Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich's ataxia.
Friedreich ataxia (FRDA) is a neurodegenerative and cardiac disease caused by GAA repeat expansions within the first intron of the FXN gene, leading to reduced frataxin expression. Frataxin is involved in iron sulfur cluster (ISC) biosynthesis, and its deficiency results in multiple cellular dysfunctions, including mitochondrial iron overload. Although altered iron homeostasis has been reported in several frataxin-deficient models and in FRDA patients, its contribution to disease progression remains debated. Here, we used a GAA expansion-based Drosophila model of FRDA, termed fh-GAAs, to investigate the impact of reducing intestinal iron absorption on disease progression. We first found that iron accumulation was tissue-specific and predominantly affected the central nervous system. Furthermore, glial cells were affected more severely than neurons, suggesting an increased vulnerability of glia to frataxin deficiency. Reducing intestinal iron uptake, either through treatment with bathophenanthroline disulfonic acid (BPS), an extracellular iron chelator, or by gut-specific silencing of the gene encoding the iron transporter Malvolio, nearly doubled fly survival. BPS treatment also improved sensitivity to dietary iron, enhanced locomotor performance, fully restored normal brain size, and prevented glial alterations. Altogether, our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the in vivo relevance of intestinal iron uptake as a potential modulator of disease severity in FRDA.
2026-07-28 | Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis.
Background: Friedreich's ataxia (FRDA) is a neurodegenerative disorder driven by frataxin deficiency, resulting in mitochondrial dysfunction and reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Pharmacologic trials have yielded inconsistent results, prompting an updated synthesis of evidence. Methods: We searched MEDLINE/PubMed, Google Scholar, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) from database inception to 29 June 2025. Embase, Scopus and Web of Science were not searched due to institutional access limitations. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Random-effects meta-analyses were conducted, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used. Primary outcomes were modified Friedreich Ataxia Rating Scale (mFARS)/Friedreich Ataxia Rating Scale (FARS); safety outcomes included adverse events (AEs) and serious AEs. Secondary outcomes were Scale for the Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS), Nine-Hole Peg Test, and the Timed 25-Foot Walk. Results: Sixteen studies (17 reports, n = 351) met inclusion criteria. Omaveloxolone was the only agent showing a statistically significant improvement in mFARS (mean difference (MD) -2.40; 95% confidence interval (CI) -4.24 to -0.56; p = 0.014), supported by low-certainty evidence. Other therapies showed no consistent benefit. Overall AE risk was comparable to control (risk ratio (RR) 1.00; 95% CI 0.98-1.03). Apparent subgroup differences by therapeutic class or age likely reflected drug-specific effects and small samples. Conclusions: Omaveloxolone was the only agent to reach statistical significance for mFARS and is the most promising and best-supported therapy among those reviewed; however, this rests on low-certainty evidence and needs confirmation in larger trials. No clear difference in overall adverse events was observed between intervention and control groups; however, available safety evidence remains limited by imprecision, small sample sizes, and short follow-up durations. Longer, standardized, and age-stratified randomized controlled trials (RCTs) are needed.
oligonucleotides
2025-12-11 | Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.
2025-10-15 | Targeting rare splicing defects: Antisense oligonucleotides offer a therapeutic strategy in FRDA
Friedreich’s ataxia (FRDA) is an autosomal recessive, multisystem disorder caused by mutations in the FXN gene, progressively affecting the nervous system, heart, and other organs.1 A recent study published in Molecular Therapy Nucleic Acids by Yameogo et al. describes a novel, intronic point mutation that disrupts canonical splicing and severely reduces FXN mRNA and frataxin protein levels.2 Using patient-derived cells, the authors demonstrated that antisense oligonucleotides (ASOs) targeting splicing regulatory elements effectively restore splicing deficits and increase frataxin expression.
2025-07-24 | Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.
Friedreich's ataxia (FRDA) is a multisystem, progressive disease. 96% of patients carry biallelic GAA triplet expansion mutations in intron 1 of the frataxin gene (FXN). The remaining 4% have a pathogenic GAA expansion on one FXN allele and another mutation on the second allele. A point mutation, FXN c.165+5G>C, was identified in intron 1 of a patient with FRDA resulting in a significant decrease of FXN levels. Using patient fibroblasts, we demonstrated that the c.165+5G>C mutation affects canonical splicing of FXN, leading to the generation of an aberrant transcript. A library of antisense oligonucleotides (ASOs) was designed to target potential intronic splicing regulator motifs and tested in patient cells. Selected O-methoxyethyl (MOE)-ASOs increased FXN levels in c.165+5G>C patient cells without affecting FXN splicing in control cells. The leading MOE-ASO increased expression of a miniFXN gene carrying the c.165+5G>C point mutation by splicing repair. To increase efficacy, we simultaneously targeted the GAA-expanded allele in patient cells using a synthetic transcription factor (synthetic transcription elongation factor 1 [Syn-TEF1]). This ASO strategy may be therapeutically feasible for patients with FRDA with other point mutations that cause splicing defects. Success in developing treatments for disorders with only a few known cases will give hope to patients with FRDA carrying these rare point mutations.
2025-06-09 | Anti-gene oligonucleotides targeting Friedreich's ataxia expanded GAA⋅TTC repeats increase Frataxin expression.
Friedreich's ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA⋅TTC triplet-repeats in the first intron of the Frataxin gene. GAA⋅TTC repeat expansion results in the formation of a non-B-DNA intramolecular triplex as well as changes in the epigenetic landscape at the Frataxin locus. Expansion of intronic GAA⋅TTC repeats is associated with reduced levels of Frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA⋅TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in Frataxin mRNA and protein levels in cells derived from Friedreich's ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA⋅TTC DNA repeats to upregulate Frataxin gene expression.
2025-03-23 | Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases.
Neurodegenerative diseases (NDD) are characterized by the progressive loss of neurons and the impairment of cellular functions. Messenger RNA (mRNA) has emerged as a promising therapy for treating NDD, as it can encode missing or dysfunctional proteins and anti-inflammatory cytokines or neuroprotective proteins to halt the progression of these diseases. However, effective mRNA delivery to the central nervous system (CNS) remains a significant challenge due to the limited penetration of the blood-brain barrier (BBB). Lipid nanoparticles (LNPs) offer an efficient solution by encapsulating and protecting mRNA, facilitating transfection and intracellular delivery. This review discusses the pathophysiological mechanisms of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), ischemic stroke, spinal cord injury, and Friedreich's ataxia. Additionally, it explores the potential of LNP-mediated mRNA delivery as a therapeutic strategy for these diseases. Various approaches to overcoming BBB-related challenges and enhancing the delivery and efficacy of mRNA-LNPs are discussed, including non-invasive methods with strong potential for clinical translation. With advancements in artificial intelligence (AI)-guided mRNA and LNP design, targeted delivery, gene editing, and CAR-T cell therapy, mRNA-LNPs could significantly transform the treatment landscape for NDD, paving the way for future clinical applications.
cell therapies
2026-09-15 | Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
2026-01-23 | Zygomatic Screws for Severe Open Bite Closure in a Young Friedreich's Ataxia Patient: A Case Report.
Friedreich's ataxia is an inherited disease affecting the nervous system and presents huge orthodontic challenges affecting the patient's coordination and muscular function. Based on the rarity of this condition, the aim of this case report is to describe an unusual orthodontic treatment employed to manage a severe open bite in a 14-year-old male patient suffering from Friedreich's ataxia, by highlighting the clinical decisions and treatment outcomes. Managing a severe anterior open bite in patients suffering from Friedreich's ataxia by skeletal anchorage mechanics for posterior teeth intrusion is advantageous considering their health condition.
2026-01-10 | Human pluripotent stem cell models of Friedreich's ataxia: innovations, considerations, and future perspectives.
Friedreich's ataxia (FRDA) is an inherited, autosomal recessive, multisystem disorder that primarily manifests in children and affects the nervous system and the heart. FRDA is caused by an expansion of GAA repeats in the first intron of the frataxin (FXN) gene. The expansion disrupts transcription of FXN, resulting in significantly decreased FXN expression in FRDA patients' tissues. Frataxin is involved in biosynthesis of iron-sulfur (Fe-S) clusters, which are critical for the function of the electron transport chain and many metabolic enzymes. Frataxin deficiency leads to reduced energy production and accumulation of iron in mitochondria that exacerbates oxidative stress. Despite significant advancements in the field, FXN cellular functions and underlying pathological mechanisms of FXN deficiency in cell-type specific contexts remain to be elucidated. Inaccessibility to the most vulnerable cell types in FRDA patients, including neurons, cardiomyocytes, and β-cells, largely accounts for these limitations. Significant progress in recent years regarding the derivation and differentiation of human pluripotent stem cells (hPSCs), along with breakthroughs in gene editing technologies, enables the generation of patient-derived and isogenic control disease-relevant cell types and organoid-like structures as platforms for studying disease mechanisms and for drug discovery. Herein, we first provide an overview of hPSC derivation and intrinsic properties of these cells. We then discuss current advances and limitations of hiPSC-based cell models for FRDA. We also highlight the need to further refine and develop these in vitro cell models for pre-clinical advancement of therapeutic approaches for FRDA.
2025-12-19 | Respiratory Function in Friedreich's Ataxia.
Friedreich's ataxia (FA) is a neurodegenerative disorder often accompanied by respiratory dysfunction, but detailed respiratory profiles remain understudied. To evaluate pulmonary parameters and respiratory muscle strength in individuals with FA compared with healthy controls. Sixteen FA patients and 20 age-matched healthy controls underwent spirometry, maximal inspiratory and expiratory pressure measurements, sniff nasal inspiratory pressure (SNIP), phrenic nerve conduction study, peripheral oxygen saturation (SpO2), and end-tidal CO2 (ETCO2). Respiratory parameters were analyzed using Student's t-test or Mann-Whitney test, and linear or quantile regression adjusted for body mass index and smoking status. Ataxia severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). FA patients exhibited significantly reduced forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), alongside decreased maximal respiratory pressures (P < 0.01). A restrictive ventilatory pattern predominated. Peripheral oxygen saturation was lower in the FA group (P < 0.01). Respiratory impairment appears mostly subclinical, suggesting that FA patients may be vulnerable to pulmonary infections and ventilatory failure. This dysfunction may reflect both neuromuscular weakness and impaired respiratory coordination. Early and regular respiratory assessment, together with preventive and rehabilitative strategies integrated into multidisciplinary care, may improve quality of life and potentially prolong survival in individuals with FA. © 2025 International Parkinson and Movement Disorder Society.
2025-02-11 | Myeloid Cell Replacement Therapy Improves Function in Friedreich Ataxia Mice by Intercellular Mitochondrial Transfer
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency, leading to neurodegeneration and cardiomyopathy. Currently, there are no effective therapies for FA. Our study investigated the potential of myeloid cell replacement using bone marrow-derived cells in the YG8-800 mouse model. Combining Busulfan myeloablation, Colony-stimulating factor 1 receptor inhibition, and bone marrow transplantation, we achieved almost complete microglia and tissue macrophage replacement. This replacement facilitated mitochondrial transfer to various CNS cells, enhancing ATP synthesis and oxidative phosphorylation and improving the mice's growth and neurobehavioral performance. Similarly, replacing macrophages restored function and increased mitochondrial activity in the heart. In vitro studies showed that transferring intact mitochondria partially restored respiratory capacity in FA cells, which had a higher uptake, suggesting a specific compensatory mechanism for mitochondrial acquisition. These findings suggest that myeloid cell replacement can promote metabolic recovery in FA through mitochondrial transfer and provide a new approach to treating FA and other mitochondrial disorders.
gene therapies
2026-09-01 | TwinPE delivered as RNA or VLP enables precise deletion of GAA repeats in the FXN gene
Friedreich’s ataxia (FRDA or FA) is a rare autosomal recessive neurodegenerative disorder caused by guanine-adenine-adenine (GAA) repeat expansions in the first intron of the frataxin ( FXN ) gene. To address this underlying genetic cause, we developed paired prime editors (twinPE) to precisely delete GAA repeats. Using a 38-bp attachment site of bacteria ( attB ) sequence as the reverse transcription template (RTT), we achieved a precise 1.2-kb deletion with attB insertion in HEK293T cells with a 48.0% editing efficiency. We further delivered two synthetic pegRNAs and PE6 mRNA into GM03816 FRDA fibroblasts and GM23404, as well as GM23913 patient-derived induced pluripotent stem cells (iPSCs) via electroporation, achieving average editing rates of 13.3%, 40.6%, and 25.0%, respectively. In both patient-derived iPSCs, twinPE successfully restored FXN expression, resulting in a ∼2-fold increase in mRNA levels, relative to non-treated controls, demonstrating a promising functional correction of gene expression. Importantly, NGS analysis revealed that >95% of all edits were precise, with minimal indels across all tested cell types. We directly delivered twinPE to iPSC-derived motor neurons (iMNs) using virus-like particles (VLPs), achieving 12.6% editing. In summary, our results demonstrate that twinPE enables efficient and precise deletion of GAA repeats across multiple cell types, including iMNs. The restoration of FXN mRNA in iPSCs represents a promising functional recovery, establishing a foundation for twinPE-mediated genome editing as a potential therapeutic strategy for FRDA.
2026-07-13 | CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives.
Huntington's disease (HD) and Friedreich's ataxia (FRDA) are progressive inherited neurodegenerative disorders caused by trinucleotide repeat expansions but characterized by distinct pathogenic mechanisms. HD arises from a coding-region CAG expansion in the HTT gene that produces toxic gain-of-function effects of mutant huntingtin (mHTT), whereas FRDA results primarily from intronic GAA repeat expansion in FXN, leading to epigenetic repression and frataxin deficiency. The emergence of CRISPR-based genome engineering has created new opportunities to address these diseases at their genetic origin. This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.
2026-04-15 | From Genetic Mutation to Therapy in Friedreich Ataxia: Molecular Mechanisms, Therapeutic Advances, and Translational Challenges
Friedreich ataxia (FRDA) is a rare, autosomal recessive, progressive neurodegenerative disorder characterized by multisystem involvement, including gait and limb ataxia, cardiomyopathy, skeletal deformities, and metabolic dysfunction. Most patients harbor biallelic GAA trinucleotide repeat expansions in intron 1 of FXN, whereas others are compound heterozygotes with a GAA expansion on one allele and a pathogenic FXN variant on the other. FXN encodes frataxin, a nuclear-encoded mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis and mitochondrial energy production. Frataxin deficiency disrupts mitochondrial metabolism, promotes iron dysregulation and oxidative stress, and leads to progressive cellular injury, particularly in high-energy tissues such as the nervous system and myocardium. Despite substantial advances in understanding FRDA pathogenesis, no curative therapy is currently available. In 2023, omaveloxolone (Skyclarys) became the first approved treatment for FRDA, marking a significant therapeutic milestone. Concurrently, disease-directed strategies have expanded rapidly, including small-molecule modulators, adeno-associated virus (AAV)-mediated gene replacement, and transcriptional or epigenetic approaches aimed at restoring endogenous FXN expression. In addition, antisense oligonucleotide-based therapies and emerging CRISPR-mediated gene editing platforms are advancing through preclinical and early clinical development. This review provides a comprehensive overview of the evolving therapeutic landscape in FRDA, highlighting mechanistic rationales, preclinical progress, clinical trial outcomes, and the key translational challenges that must be addressed to achieve durable disease modification.
2026-01-28 | Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review.
Neurodevelopmental disorders (NDDs) with ataxia are genetically heterogeneous and remain a diagnostic challenge. Recent advances in genomic technologies have facilitated the identification of rare, potentially causative variants in genes not traditionally associated with classic NDD phenotypes. The DNAH14 gene, encoding a dynein axonemal heavy chain involved in ciliary motility, has recently emerged as a novel candidate in neurological syndromes. Here, we report two Turkish siblings presenting with late-onset balance disorder, progressive ataxia, and cognitive impairment. Initial genetic analysis revealed that both siblings also harbor FXN GAA repeat expansions consistent with pathogenic Friedreich's ataxia (FRDA). To elucidate the molecular basis of the patients' cognitive impairment, whole-exome sequencing was performed. This analysis identified a novel homozygous frameshift variant in the DNAH14 gene, located within the conserved linker domain upstream of the motor core, which is critical for ATP hydrolysis and microtubule interactions. The variant is absent from population databases, predicted to be deleterious by multiple in silico algorithms, and segregates in the family in a manner consistent with autosomal recessive inheritance. The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.
2025-11-30 | Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.
other
2026-09-08 | Mitochondrial Quality Control as the Mechanistic Hinge of Inherited Cardiomyopathy: Convergent Pathobiology and Targeted Therapy
Inherited mitochondrial cardiomyopathies arise from pathogenic variants that disrupt oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin biogenesis, or mitochondrial dynamics and quality control. Although the causative genes are diverse—mtDNA mutations, nuclear respiratory-chain and assembly factors, TAZ in Barth syndrome, FXN in Friedreich ataxia, AGK in Sengers syndrome—the resulting cardiac disease converges on a shared endpoint: bioenergetic insufficiency with cristae destabilization, calcium mishandling, redox imbalance, and failure of mitophagy-dependent quality control. We synthesize how these distinct lesions funnel into common pathways of hypertrophy, fibrosis, and arrhythmogenesis, and argue that this convergence, rather than any single gene, defines the actionable therapeutic space. Mapping treatment onto these nodes, we discuss cardiolipin-directed stabilization with elamipretide—approved for Barth syndrome in 2025—gene-replacement and editing strategies (AAV-delivered TAZ and FXN, mitochondrial base editing), and cofactor, substrate-bypass, and mitophagy-modulating approaches. We propose a falsifiable central hypothesis with testable predictions, and confront the field’s principal obstacles: genetic heterogeneity requiring patient stratification, an apparent fibrotic ceiling on reversibility, and mitochondrial delivery barriers. Positioning mitochondrial quality control as the mechanistic hinge, we outline a stratified, mechanism-guided route toward cardiac-specific therapy.
2026-08-10 | Impaired Glur2 palmitoylation in cerebellar Purkinje cells of a Friedreich ataxia mouse model.
Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by frataxin deficiency, characterized by progressive cerebellar dysfunction and neuronal loss. Although synaptic abnormalities are an early feature of FRDA, the molecular mechanisms linking frataxin deficiency to synaptic dysfunction remain incompletely defined. In this study, we investigated post-translational regulation of the AMPA receptor subunit GluR2 in the cerebellum of the frataxin knockdown (FRDAkd) mouse model. GluR2 protein levels are reduced early following frataxin knockdown, despite unchanged mRNA expression and preserved Purkinje cell number. Phosphorylation of GluR2 at regulatory sites (Ser880 and Tyr876) is unchanged relative to total protein, indicating that altered phosphorylation does not account for reduced GluR2 levels. In contrast, acyl-biotin exchange assays and proximity ligation analysis reveal a significant reduction in GluR2 palmitoylation, localized primarily to Purkinje cell somata. This deficit is selective, as palmitoylation of other synaptic proteins is variably affected. Mechanistically, reduced GluR2 palmitoylation associates with decreased expression and palmitoylation of the palmitoyl acyltransferase DHHC3, while levels of depalmitoylating enzymes remain unchanged. In vitro, DHHC3 enhances GluR2 palmitoylation, supporting a direct enzymatic relationship. Partial restoration of frataxin expression rescues GluR2 and DHHC3 protein levels and partially restores GluR2 palmitoylation. These findings identify impaired GluR2 palmitoylation as an early, selective synaptic alteration in FRDA and implicate dysregulated lipid-dependent post-translational modification as a mechanism linking frataxin deficiency to cerebellar synaptic vulnerability.
2026-06-17 | Genetic modifiers of Friedreich's ataxia pathophysiology in Drosophila melanogaster - A systematic review and meta-analysis.
Friedreich's ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by reduced frataxin protein levels. Depleted frataxin leads to mitochondrial dysfunction, elevated oxidative stress and progressive neurodegeneration. The molecular mechanisms that regulate the severity of disease are still poorly understood. Genetic modifiers have proved to be important determinants of the disease pathophysiology and in uncovering novel therapeutic targets. This systematic review and meta-analysis was conducted to compare the effectiveness of different genetic modifiers of the pathophysiology of the FRDA in Drosophila model. Articles were screened as per PICO criteria and included articles were assessed for methodological quality using SYRCLE tool and plotted using robvis tool. Genetic modifiers improved survival (effect size (ES) 0.2082), brain vacuolization, Electroretinogram (ERG) (ES 0.6373), locomotion (ES 0.3356), and aconitase activity (ES 0.2087), of Drosophila FRDA models while the heterogeneity was high across different studies for all phenotypes. Genetic modifiers were compared on the basis of efficacy, reproducibility, mechanistic relevance, safety, therapeutic plausibility and graded for their effectiveness on disease pathogenicity. Ferritins overexpression, Miro inhibition, and catalase overexpression, converging pathways iron homeostasis, mitochondrial dynamics and oxidative stress management, were found to be the top ranked modifiers for their beneficial effects on FRDA pathophysiology and were suggested for further studies as therapeutic targets. Based on the limitations identified in this systematic review and meta-analysis, we recommend that subsequent research studies adopt standardized reporting practices, multiple phenotype validation, supporting behavioural outcomes with biochemical and cellular readouts, using genetically precise models and systematic sharing of raw data to enhance reproducibility and research value.
2026-05-19 | Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
Recent discoveries reveal that frataxin (FXN) and ferredoxin 2 (FDX2) competitively regulate mitochondrial iron-sulfur (Fe-S) cluster biosynthesis through their binding to the cysteine desulfurase NFS1 and the iron-sulfur cluster scaffold protein ISCU2 complex. Here, we discuss the potential of rationally designed peptide inhibitors targeting the FDX2-NFS1 interaction as a strategy to mitigate FXN deficiency and restore Fe-S cluster biosynthesis.
2026-01-21 | Integration of Evolutionary Analysis With RFdiffusion for De Novo Design of Aggregation-Resistant Frataxin.
Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by frataxin (FXN) deficiency, where protein replacement therapy is hampered by the inherent instability and aggregation propensity of wild-type (WT) FXN. The structural flexibility of Loop-1 (residues 115-123), a critical region within the acidic ridge, represents a key determinant of protein stability. This study introduces a computational pipeline integrating evolutionary conservation analysis (ConSurf) with diffusion-based de novo design (RFdiffusion) to redesign both the backbone and sequence of Loop-1. Through systematic filtration of 1000 ProteinMPNN-generated variants using aggregation propensity screening (AGGRESCAN) and 450 ns of molecular dynamics (MD) simulations, four lead candidates were identified. Design_188 (EERVGGREI) demonstrated optimal performance with 2.3-fold improvement in aggregation resistance (Na4vSS: -53.8 vs. -23.5 for WT), superior structural stability (RMSD: 0.486 nm), reduced conformational diversity (62.3% dominant cluster occupancy), and 93% retention of ISCU binding capacity (ΔΔG: +6.4 kcal/mol). Experimental validation through 15N NMR relaxation analysis confirmed computational predictions, with Design_188 exhibiting uniform backbone rigidification (S2 = 0.81-0.95) and strong MD-NMR correlation (Pearson r = 0.675, p = 0.003). SEC-MALS analysis demonstrated near-complete monomeric behavior (> 98% monomer content) compared to WT's heterogeneous oligomerization (68% monomer, 32% oligomers), directly confirming the predicted anti-aggregation properties. K-means clustering analysis revealed an inverse relationship between conformational heterogeneity and stability, while correlation analysis identified a fundamental trade-off between aggregation resistance and structural stability (r = -0.82, p < 0.01). This work establishes a generalizable framework for therapeutic protein engineering where backbone redesign enables conformational ensemble modulation beyond the limitations of sequence optimization alone.
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Drug Discovery Landscape
36 orphan drug designations for Friedreich ataxia, including 2 approved therapies.
36 orphan drug designations for Friedreich ataxia, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant adeno-associated virus (AAV) vector encoding the human frataxin (hFXN) gene | gene therapies | FDA | — | Neurocrine Biosciences, Inc. |
recombinant non-replicating adeno-associated virus serotype hu68 containing a codon-optimized cDNA that encodes the consensus sequence of the human frataxin protein | gene therapies | FDA | Solid Biosciences Inc. | |
recombinant adeno-associated virus serotype 8 expressing codon optimized human frataxin gene cDNA under the control of a ubiquitous hPGK promoter (rAAV8-hPGK-hFXNco) | gene therapies | FDA | — | Astellas Gene Therapies, Inc. |
autologous human CD34+ hematopoietic stem and progenitor cells isolated from mobilized peripheral blood stem cell of patients with Friedreich's ataxia, modified ex vivo using CRISPR/Cas9 technology to remove the GAA hyper-expansion mutation in the intron 1 of frataxin | gene editing enzymes | FDA | — | Papillon Therapeutics Inc. |
Adeno-associated virus vector serotype rh.10 containing the human FXN gene | gene therapies | EMA | — | Scendea (NL) B.V. |
elamipretide | peptides | FDA | Stealth Biotherapeutics, Inc. | |
Adeno-associated viral vector encoding the human frataxin (FXN) gene, AAVrh.10hFXN | gene therapies | FDA | Lexeo Therapeutics | |
Zaftuclenegene piruparvovec | gene therapies | EMA | — | [INACTIVE] Novartis Gene Therapies EU Limited |
Vatiquinone | small molecules | EMA | PTC Therapeutics International Limited | |
AAV9 gene vector construct expressing the human Frataxin gene (scAAV9.CB.hFRXN isoform 1) | gene therapies | FDA | Novartis Institute for BioMedical Research, Inc. | |
Human frataxin fused to TAT cell-penetrating peptide | proteins | EMA | Yes Pharmaceutical Development Services GmbH | |
Leriglitazone | small molecules | EMA | Minoryx Therapeutics S.L. | |
leriglitazone | small molecules | FDA | Minoryx Therapeutics S.L. | |
Luvadaxistat | small molecules | EMA | Takeda Pharma A/S | |
Omaveloxolone [Skyclarys] | small molecules | EMA | Approved | Biogen Netherlands B.V. |
Dimethyl fumarate | small molecules | EMA | Qualix Pharma S.L. | |
D-amino acid oxidase inhibitor | small molecules | FDA | Takeda Development Center Americas, Inc. | |
Recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein | gene therapies | EMA | — | PTC Therapeutics International Limited |
trans-resveratrol | small molecules | FDA | Jupiter Orphan Therapeutics | |
Fusion protein linking human frataxin to a cell-penetrant peptide | proteins | FDA | Larimar Therapeutics, Inc. | |
omaveloxolone [Skyclarys] | small molecules | FDA | Approved | Biogen U.S. Corporation |
recombinant, adeno-associated virus serotype 5 vector, containing the transgene, which encodes for the human protein, frataxin | gene therapies | FDA | PTC Therapeutics, Inc. | |
9-cis, 12-cis-11,11-d2-linoleic acid ethyl ester | small molecules | FDA | Retrotope, Inc. | |
interferon gamma-1b | proteins | FDA | Horizon Therapeutic Ireland DAC | |
vatiquinone | small molecules | FDA | PTC Therapeutics, Inc. | |
dimethyl fumarate | small molecules | FDA | Ixchel Pharma, LLC | |
Interferon gamma | proteins | EMA | Horizon Therapeutics Ireland Designated Activity Company | |
interferon gamma | proteins | FDA | Roberto Testi, MD | |
coenzyme Q10 and d-alpha-tocopherol | small molecules | FDA | — | NBI Pharmaceuticals, Inc. |
N-(6-(2-aminophenylamino)-6-oxohexyl)-4-methylbenzamide | small molecules | EMA | — | Repligen Europe Limited |
N-(6-2-aminophenylamino)-6-oxohexyl)-4-methylbenzamide | small molecules | FDA | — | Repligen Corporation |
deferiprone | small molecules | FDA | Chiesi USA, Inc. | |
idebenone | small molecules | FDA | Chiesi Farmaceutici S.p.A. | |
Idebenone | small molecules | EMA | Chiesi Farmaceutici S.p.A. | |
Idebenone | small molecules | EMA | Laboratoires Takeda | |
physostigmine salicylatephysostigmine salicylate | small molecules | FDA | — | Forest Pharmaceuticals.3-.3-.30 6 |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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