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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.


Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Cerebellar neuropathology in FRDA patients includes loss of large principal neurons and synaptic terminals in the dentate nucleus (DN) and previous studies have demonstrated early synaptic deficits in the Knockin-Knockout mouse model of FRDA. However, the exact correlation of frataxin deficiency with cerebellar neuropathology remains unclear. Here the authors report that doxycycline-induced frataxin knockdown in a mouse model of FRDA (FRDAkd) leads to synaptic cerebellar degeneration that can be partially reversed by AAV8-mediated frataxin restoration. Loss of cerebellar Purkinje neurons and large DN principal neurons are observed in the FRDAkd mouse cerebellum. Levels of the climbing fiber-specific glutamatergic synaptic marker VGLUT2 decline starting at 4 weeks after dox induction, whereas levels of the parallel fiber-specific synaptic marker VGLUT1 are reduced by 18-weeks. These findings suggest initial selective degeneration of climbing fiber synapses followed by loss of parallel fiber synapses. The GABAergic synaptic marker GAD65 progressively declined during dox induction in FRDAkd mice, while GAD67 levels remained unaltered, suggesting specific roles for frataxin in maintaining cerebellar synaptic integrity and function during adulthood. Expression of frataxin following AAV8-mediated gene transfer partially restored VGLUT1/2 levels. Taken together, these findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function.

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Informational Webinar on CDRMP Funding Opportunities

New Funding Opportunities for Friedreich Ataxia Research from the DoD
Webinar - Tuesday, April 5, 2022

The Friedreich's Ataxia Research Alliance (FARA) and the National Ataxia Foundation (NAF) held an informational webinar on April 5, 2022 with Cecilia Dupecher, Ph.D, Program Manager for the Peer Reviewed Medical Research Program (PRMRP). The PRMRP is within the Department of Defense’s Congressionally Directed Medical Research Programs (CDMRP) - a global funding organization that fosters novel approaches to congressionally targeted biomedical research areas. CDMRP receives annual appropriations that are disease or condition-specific and for the FY22 budget has added Friedreich Ataxia to the list of topic areas eligible for $370M in funding within the PRMRP. Dr. Dupecher reviewed available funding opportunities, offered guidance on the application process, and answered questions.

View the Webinar Recording

The following mechanisms provide funding opportunities for Friedreich Ataxia research:

  • Clinical Trial Award: Supports the rapid implementation of clinical trials of novel interventions. Preproposal deadline is May 6, 2022 5:00 p.m. ET
  • Discovery Award: Supports the exploration of a highly innovative new concept or untested theory - Letter of Intent deadline is April 22, 2022 5:00 p.m. ET
  • Focused Program Award: Supports a synergistic, multidisciplinary research program of at least four distinct but complementary projects addressing an overarching goal/question – Preproposal deadline is May 6, 2022 5:00 p.m. ET
  • Investigator-Initiated Research Award: Supports research that will make an original and important contribution to the field of research or patient care in the Topic Area(s) of interest - Letter of Intent deadline is April 29, 2022 5:00 p.m. ET
  • Technology/Therapeutic Development Award: Supports the translation of promising preclinical findings into clinical applications for prevention, detection, diagnosis, treatment, and/or quality of life - Letter of Intent deadline is April 29, 2022 5:00 p.m. ET
All organizations, including foreign organizations, foreign public entities, and international organizations, are eligible to apply.

More Information

Submit Your Pre-Application

 
 

Bone Mineral Density and Current Bone Health Screening Practices in Friedreich's Ataxia

Impaired bone health is a complication of disorders affecting mobility, but there is little information regarding bone health in FRDA. Dual energy X-ray absorptiometry (DXA) scan-based assessments of areal bone mineral density (aBMD) in individuals with FRDA were abstracted from four studies at the Children's Hospital of Philadelphia (CHOP). Disease outcomes, including the modified FRDA Rating Scale (mFARS), were abstracted from the FRDA Clinical Outcomes Measures Study (FACOMS), a longitudinal natural history study. A survey regarding bone health and fractures was sent to individuals in FACOMS-CHOP. Adults with FRDA (n = 24) have lower mean whole body (WB) (-0.45 vs. 0.33, p = 0.008) and femoral neck (FN) (-0.71 vs. 0.004, p = 0.02) aBMD Z-scores than healthy controls (n = 24). Children with FRDA (n = 10) have a lower WB-less-head (-2.2 vs. 0.19, p < 0.0001) and FN (-1.1 vs. 0.04, p = 0.01) aBMD than a reference population (n = 30). In adults, lower FN aBMD correlated with functional disease severity, as reflected by mFARS (R = -0.56, p = 0.04). Of 137 survey respondents (median age 27 y, 50% female), 70 (51%) reported using wheelchairs as their primary ambulatory device: of these, 20 (29%) reported a history of potentially pathologic fracture and 11 (16%) had undergone DXA scans. Low aBMD is prevalent in FRDA, but few of even the highest risk individuals are undergoing screening. These findings highlight potential missed opportunities for the screening and treatment of low aBMD in FRDA.

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Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention

The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transition metal. Although a mechanistic understanding of the link between brain iron accumulation (BIA) and neurodegenerative diseases is lacking, BIA is co-morbid with the majority of cognitive and motor function disorders. The most prevalent neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), and Multiple Sclerosis (MS), often present with increased deposition of iron into the brain. In addition, ataxias that are linked to mutations in mitochondrial-localized proteins (Friedreich's Ataxia, Spinocerebellar Ataxias) result in mitochondrial iron accumulation and degradation of proton-coupled ATP production leading to neuronal degeneration. A comorbidity common in the elderly is a chronic systemic inflammation mediated by primary cytokines released by macrophages, and acute phase proteins (APPs) released subsequently from the liver. Abluminal inflammation in the brain is found downstream as a result of activation of astrocytes and microglia. Reasonably, the iron that accumulates in the brain comes from the cerebral vasculature via the microvascular capillary endothelial cells whose tight junctions represent the blood-brain barrier. A premise amenable to experimental interrogation is that inflammatory stress alters both the trans- and para-cellular flux of iron at this barrier resulting in a net accumulation of abluminal iron over time. This review will summarize the evidence that lends support to this premise; indicate the mechanisms that merit delineation; and highlight possible therapeutic interventions based on this model.

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Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.

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