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Research IconFARA Funded Research

Your generous support has funded all the research listed below.

For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes

Frataxin functions in the biogenesis of iron-sulfur clusters, which are prosthetic groups that are found in proteins involved in many biological processes. To study the changes associated with decreased frataxin in human cardiomyocytes, the authors developed a novel isogenic model by acutely knocking down frataxin, post-differentiation, in cardiomyocytes derived from induced pluripotent stem cells. Transcriptome analysis of four biological replicates identified severe mitochondrial dysfunction and a type I interferon response as the pathways most affected by frataxin knockdown. In iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.

Read the Full article here

Frataxin controls ketone body metabolism through regulation of OXCT1

This study shows that frataxin controls ketone body metabolism through regulation of 3-Oxoacid CoA-Transferase 1 (OXCT1), a rate limiting enzyme catalyzing the conversion of ketone bodies to acetoacetyl-CoA that is then fed into the Krebs cycle. Biochemical studies show a physical interaction between frataxin and OXCT1 both in vivo and in vitro. Frataxin overexpression also increases OXCT1 protein levels in human skin fibroblasts while frataxin deficiency decreases OXCT1 in multiple cell types including cerebellum and skeletal muscle both acutely and chronically, suggesting that frataxin directly regulates OXCT1. This regulation is mediated by frataxin-dependent suppression of ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. Concomitantly, plasma ketone bodies are significantly elevated in frataxin deficient knock-in/knockout (KIKO) mice with no change in the levels of other enzymes involved in ketone body production. In addition, ketone bodies fail to be metabolized to acetyl-CoA accompanied by increased succinyl-CoA in vitro in frataxin deficient cells, suggesting that ketone body elevation is caused by frataxin-dependent reduction of OXCT1 leading to deficits in tissue utilization of ketone bodies. Considering the potential role of metabolic abnormalities and deficiency of ATP production in FRDA, these results suggest a new role for frataxin in ketone body metabolism and also suggest modulation of OXCT1 may be a potential therapeutic approach for FRDA.

Read the Full article here

Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation

Clinical trials in rare diseases as Friedreich ataxia (FRDA) offer special challenges, particularly when multiple treatments become ready for clinical testing. Regulatory health authorities have developed specific pathways for "orphan" drugs allowing the use of a validated biomarker for initial approval. This study aimed to identify changes in cerebrospinal fluid (CSF) proteins occurring in FRDA patients that may be potential biomarkers in therapeutic trials. CSF was obtained from 5 FRDA patients (4 females, 1 male) from the Brussels site of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS). Two patients were ambulatory, three used a wheelchair. Residual CSF samples from 19 patients who had had a lumbar puncture as part of a diagnostic workup were used as controls. All CSF samples had normal cells, total protein and glucose levels. Proteins were identified by label-free data-dependent acquisition mass spectrometry (MS) coupled to micro-high performance liquid chromatography. The authors found 172 differentially expressed proteins (DEPs) (92 up, 80 down) between FRDA patients and controls at P < 0.05, 34 DEPs (28 up, 6 down) at P < 0.0001. Remarkably, there was no overlap between FRDA patients and controls for seven upregulated and six downregulated DEPs. Represented pathways included extracellular matrix organization, signaling, the complement cascade, adhesion molecules, synaptic proteins, neurexins and neuroligins. This study supports the hypothesis that the quantitative analysis CSF proteins may provide robust biomarkers for clinical trials as well as shed light on pathogenic mechanisms. Interestingly, DEPs in FA patients CSF point to neurodegeneration and neuroinflammation processes that may respond to treatment.

Read the Full article here

Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia

To provide a better understanding of the metabolic status of FRDA patients, the authors used patient-derived fibroblast cells as a surrogate tissue for metabolic and lipidomic profiling by liquid-chromatography high resolution-mass spectrometry (LC-HRMS). They found elevated HMG-CoA and β-hydroxybutyrate (BHB)-CoA levels, implying dysregulated fatty acid oxidation, which was further demonstrated by elevated acyl-carnitine levels. Lipidomic profiling identified dysregulated levels of several lipid classes in FRDA fibroblast cells when compared with non-FRDA fibroblast cells. For example, levels of several ceramides were significantly increased in FRDA fibroblast cells; these results positively correlated with the GAA repeat length and negatively correlated with the frataxin protein levels. Furthermore, stable isotope tracing experiments indicated increased ceramide synthesis, especially for long chain fatty acid-ceramides, in FRDA fibroblast cells compared to ceramide synthesis in healthy control fibroblast cells. In addition, PUFA containing triglycerides and phosphatidylglycerols were enriched in FRDA fibroblast cells and negatively correlated with frataxin levels, suggesting lipid remodeling as a result of FXN deficiency. Altogether, we demonstrate patient-derived fibroblast cells exhibited dysregulated metabolic capabilities, and their lipid dysfunction predicted the severity of FRDA, making them a useful surrogate to study the metabolic status in FRDA.

Read the Full article here

Meet the team at University of Florida for the TRACK-FA Study

Track FA Study Team Photo
Who are the team members?
Manuela Corti, PhD; Asst Professor of Pediatrics and Associate Director of Powell Gene Therapy Center
S H Subramony, MD; Professor of Neurology and Pediatrics
Thomas Mareci, PhD; Professor, Department of Biochemistry and Molecular Biology
Mackenzi Coker, MS, CCC-SLP; Clinical Research Coordinator, Department of Pediatrics
Samantha Norman, MPH, BS; Clinical Research Coordinator, Department of Pediatrics

How long has the UF Team been working on FA?
Dr. Corti has worked on FA for over 10 years based on her interests in bringing gene therapy to several neuromuscular disorders. Dr. Subramony has been involved with FA for over 25 years as part of broad interest in inherited ataxias and was instrumental in developing early outcome measures. Dr. Mareci is an expert in MRI technology and has worked on imaging studies of ataxias for over 5 years. Mackenzie Coker and Sam Norman bring expertise in clinical research coordination in genetic diseases

Who was the first fellow FA researcher you met?
Dr. Subramony was the first FA researcher that Dr. Corti met. During the last 10 years, she has interacted with other FA researchers in the United States, Australia and Europe. Dr. Subramony has interacted with many FA researchers for many years including Drs Lynch, Perlman and Bidichandani and has been member of Collaborative Clinical Research Network in FA since its conception.

What got you interested in FA research?
Dr. Corti started a gene therapy program with Dr. Barry Byrne, the Powell Gene Therapy Center’s director, in FA after the mother of an FA affected individual, approached them about working toward developing gene therapy for FA. Through a community fundraiser, a pilot research program was initiated at the University of Florida. The UF FA research team has since been awarded multiple grants from patient foundations and industry partners. The ultimate aim of the program is to bring direct gene replacement to FA patients, at the same time offering opportunities for other research studies and clinical trials. These efforts are helped by the excellent facilities at UF, especially the Powell Gene Therapy Center (PGTC) and Clinical and Translational Science Institute (CTSI).

Dr. Subramony became involved in genetic ataxias in the late 1980s and 1990s, oversaw one of the early ataxia focused clinics at the University of Mississippi and evaluated and genotyped many families with FA and SCAs. After coming to UF in 2009, it was a natural event to collaborate with the Powell Gene Therapy Center.

What got you interested in imaging in FA?
Having realized the limitations of clinical outcome measures in FA, there is major interest in biomarkers with imaging being a prime candidate. At UF, this interest could be fostered easily by the presence of the research only facility, Advanced Magnetic Resonance Imaging and Spectroscopy facility (AMRIS), and the scientists associated with it. Dr. Mareci had already participated in multi-center MRI studies of spinocerebellar ataxias. This expertise was easily adapted for the TRACK-FA study. TRACK-FA is one of a number of other research imaging studies in genetic neuromuscular diseases at AMRIS, including cardiac imaging in FA.

What do you hope to achieve with TRACK-FA?
We fervently hope that the findings in this study will speed up and facilitate upcoming clinical trials of novel therapeutics including gene therapy in FA.

How would you like to encourage FA patients to participate at your site?
Gainesville is a wonderful “college” town with many sporting and cultural activities associated with the university. There are many museums and restaurants and if you time your visit, you can watch competitive University sports such as football. TRACK-FA visits take place in the Clinical and Translational Science building, a state-of-the-art research building which is uncluttered and pleasant, and the AMRIS imaging facility which is also utilized for research only and is beautiful in its own regards. Don’t forget that you can add a Florida vacation to your trip by driving to one the of beaches or to one of the many amusement parks in Orlando, all within 100 miles of Gainesville.

In addition, all FA patients coming to UF become family to us. We do everything we can to help FA patients to overcome some of the challenges that come with living with FA. We are always available to communicate with their medical providers, if needed, we are willing to help in identifying the best exercise program for them, we help with patient equipment needs to enhance safety and maintain autonomy. Furthermore, we are always available to discuss scientific questions related to upcoming research. And most importantly, we are always here for a laugh, a cry and simply for a chat.

How would a TRACK-FA visit look like at your site?
If coming for a TRACK-FA visit, you can look forward to a quality visit with our team. If it is your first visit to our site, you will be consented into the study by one of our study team members. From there we will collect some medical information, including your genetic confirmation and any medications you may be taking. We will then get some vitals as well as collect some blood from you.

Once the boring things are out of the way, we will then move into the functional and cognitive assessments. These assessments include the run of the mill mFARs, the SARA, the 9hpt, vision and speech testing. The cognitive assessments will include three brief questionnaires and we will discover your handedness. Your visit will be rounded out with the MRI which includes imaging of both the brain and spinal cord.

Read more about the study HERE

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