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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.


Three Adult-Onset Autosomal Recessive Ataxias: What Adult Neurologists Need to Know

This review seeks to raise awareness of 3 autosomal recessive ataxias that look different clinically when presenting in adulthood rather than childhood. A study found a high allelic frequency for repeat expansions in the RFC1 gene, a cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, which presents exclusively in adults. This implies that autosomal recessive etiologies of adult-onset cerebellar ataxias may be more common than previously thought. Adult-onset cerebellar ataxias are commonly caused by mutations inherited in either an autosomal dominant or X-linked pattern, as most autosomal recessive mutations cause disease at earlier ages. However, some autosomal recessive etiologies such as late-onset Tay-Sachs disease, very late-onset Friedreich ataxia, and autosomal recessive spastic ataxia of Charlevoix-Saguenay emerge in adulthood, with age at presentation influencing the progression and clinical signs of the disease. This review will cover the genetics, clinical presentation, and necessary diagnostic steps required to identify 3 causes of autosomal recessive cerebellar ataxia that manifest differently in adults vs children.

Read the Full article here
 

Request For Proposals: Pharmacodynamic Biomarker Development

Request For Proposals: Pharmacodynamic Biomarker Development
FARA is issuing a request for proposals (RFP) to support clinical drug development programs in Friedreich’s ataxia (FRDA) by promoting the discovery of technologies to measure frataxin or surrogates of frataxin in inaccessible and disease relevant tissues.

This RFP supports the discovery and validation of non-invasive and quantitative methodologies to measure the following in FRDA affected tissues (brain, spinal cord or heart):
  • Frataxin protein levels
  • Biochemical activities dependent on/downstream of frataxin function that can be surrogates of frataxin in inaccessible tissues
Allowed budget will depend on stage and scope of research.

FARA will consider proof of concept and high-risk proposals, without preliminary data, provided they show a strong rationale for the proposed use and development of such biomarkers.

Informal inquiries regarding study relevance and interest to FARA are welcome and should be directed to grants@curefa.org.
Read the Full RFP

Please click below to submit a Letter of Intent.The LOI submission deadline is December 1, 2021.
Submit a Letter of Intent

 

Neuro-Ophthalmological Findings in Friedreich's Ataxia

This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.

Read the Full article here
 

Brain Structure and Degeneration Staging in Friedreich Ataxia: MRI Volumetrics from the ENIGMA-Ataxia Working Group

This group of investigators undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, inter-individual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed greatest reductions in volume relative to controls (Cohen's d = 1.5-2.6). Cerebellar grey matter alterations were most pronounced in lobules I-VI (d = 0.8), while cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax = 0.35) and peduncles (rmax = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral grey matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated inter-individual variability in brain measures.

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Mechanisms of impaired mitochondrial homeostasis and NAD + metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation

Previous studies identified defective mitochondrial iron metabolism and oxidative stress potentiating cardiac pathology in FA. However, how these factors alter mitochondrial homeostasis remains uncharacterized in FA cardiomyopathy. This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.

Read the Full article here
 

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