The aim of this work was to investigate whether anodal cerebellar transcranial direct current stimulation (ctDCS) reduces ataxic and cognitive symptoms in individuals with Friedreich's ataxia (FRDA) and to assess the effects of ctDCS on the activity of the secondary somatosensory (SII) cortex. The authors performed a single-blind, randomized, sham-controlled, crossover trial with anodal ctDCS (5 days/week for 1 week, 20 min/day, density current: 0.057 mA/cm2 ) in 24 patients with FRDA. Each patient underwent a clinical evaluation (Scale for the Assessment and Rating of Ataxia, composite cerebellar functional severity score, cerebellar cognitive affective syndrome scale) before and after anodal and sham ctDCS. Activity of the SII cortex contralateral to a tactile oddball stimulation of the right index finger was evaluated with brain functional magnetic resonance imaging at baseline and after anodal/sham ctDCS. Anodal ctDCS led to a significant improvement in the Scale for the Assessment and Rating of Ataxia (-6.5%) and in the cerebellar cognitive affective syndrome scale (+11%) compared with sham ctDCS. It also led to a significant reduction in functional magnetic resonance imaging signal at the SII cortex contralateral to tactile stimulation (-26%) compared with sham ctDCS. One week of treatment with anodal ctDCS reduces motor and cognitive symptoms in individuals with FRDA, likely by restoring the neocortical inhibition normally exerted by cerebellar structures. This study provides class I evidence that ctDCS stimulation is effective and safe in FRDA.
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Scientific News
FARA funds research progress
In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA's Grant Program and the Treatment Pipeline.
Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial
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LEXEO Therapeutics Announces Completion of First Cohort and Dosing in Second Cohort in Sunrise-fa, A Phase 1/2 Clinical Trial of Lx2006 for The Treatment of Friedreich’s Ataxia Cardiomyopathy
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LEXEO Therapeutics Announces Completion of First Cohort and Dosing in Second Cohort in SUNRISE-FA, a Phase 1/2 Clinical Trial of LX2006 for the Treatment of Friedreich’s Ataxia Cardiomyopathy.
In the first dose cohort, LX2006 has been well tolerated with no unexpected events or toxicities observed. Following the Data Safety Monitoring Board recommendation to proceed, investigators have initiated dosing in the second cohort.
“New treatment approaches, like LEXEO’s LX2006 gene therapy candidate, are critical for individuals and caregivers confronted with the debilitating realities of FA,” said Friedreich’s Ataxia Research Alliance Chief Executive Officer Jennifer Farmer. “Cardiomyopathy is the leading cause of death in individuals diagnosed with FA, so we are incredibly encouraged by the work that LEXEO has undertaken to try to address this life-threatening complication through gene therapy. We are grateful to all the individuals in the FA community who volunteer and participate in research studies and clinical trials.”
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Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials
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Tiberi J, Segatto M, Fiorenza MT, La Rosa P.
FXN deficiency in FRDA perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signaling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signaling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, the authors overview the outcomes obtained with the administration of various antioxidant compounds and critically analyze the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
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Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines
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Yadav S, Waldeck-Weiermair M, Spyropoulos F, Bronson R, Pandey AK, Das AA, Sisti AC, Covington TA, Thulabandu V, Caplan S, Chutkow W, Steinhorn B, Michel T.
Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here the authors report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's ataxia. These observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich's ataxia.
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Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich's ataxia
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- Category: Funded Research
Ast T, Wang H, Marutani E, Nagashima F, Malhotra R, Ichinose F, Mootha VK.
The authors previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular they showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. This study reports the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical, and effective regimen for clinical translation. Three chief results are reported. First, a daily, intermittent hypoxia regimen (16 hours 11% O2/8 hours 21% O2) conferred no benefit, and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as this toxicity could be blunted by pharmacologically inhibiting polycythemia. Second, more mild regimens of chronic hypoxia (17% O2) confers a modest benefit by delaying the onset of ataxia. Third, excitingly, initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. These studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.
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- Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers
- A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia
- Larimar Therapeutics Reported Preliminary Top-line Data from Phase 2 Trial’s 25 mg Cohort Showing Increases in Frataxin Levels in Patients with Friedreich’s Ataxia
- PTC Therapeutics Announces Topline Results from Vatiquinone MOVE-FA Registration-Directed Trial
- Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia