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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.

Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia

Friedreich's ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at the FXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here the authors describe a family whose proband was affected by late-onset Friedreich's ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband's unaffected sister, as well as their healthy mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66-67 repeat mimicking a GAA expansion at the LR-PCR that was the cause of the wrong initial diagnosis of pre-symptomatic LOFA. Extensive studies in tissues from all the family members, including LR-PCR, assessment of methylation status of FXN locus, MboII restriction analysis and direct sequencing of LR-PCR products, analysis of FXN mRNA, and frataxin protein expression, support the virtual lack of pathogenicity of the rare (GAAGGA)66-67 repeat, also providing significant data about the modulation of epigenetic modifications at the FXN locus. Overall, this report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.

Read the entire article HERE

Trinucleotide Repeat Disorders

Trinucleotide repeat disorders consist of a group of human diseases, which are a result of an abnormal expansion of repetitive sequences and primarily affect the nervous system. These occur during various stages of human development. Repetitive sequences, scattered in the microsatellite regions, usually account for about 30% of the human genome. In a normal person, the main purpose of various lengths of repetitive DNA is to allow for evolutionary plasticity. However, when these repeats extend beyond the code for a viable physiological protein, the expression of this aberrant segment is suppressed. After a certain threshold number, this suppression is lost, and an aberrant protein is coded for, which gives rise to either a functional or a non-functional protein, thereby giving rise to a 'gain of function' or 'loss of function' mutation. With every generation, the number of repeats increases drastically, and the age at which the patient presents is inversely related to the number of expansions. The severity, on the other hand, worsens with every generation due to a larger repeat sequence. Thus, the inheritance pattern of the repeat expansion diseases is evidence of the dynamic nature of these mutations and is termed as 'anticipation'. Myotonic dystrophy (DM), Huntington disease, spinocerebellar ataxia, Friedreich ataxia, and fragile X syndrome fall under the spectrum of trinucleotide repeat disorders. This article will study the various parameters of trinucleotide repeat disorders by reviewing in detail the five most commonly studied disorders, as listed above.

Read the entire article HERE

Stress-induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

Although cardiac dysfunction is the most common cause of mortality in Friedreich's ataxia (FA), the cardiac disease remains subclinical for most of the clinical course because the neurologic disease limits muscle oxygen demands. Previous FXN knockout mouse models exhibit fatal cardiomyopathy similar to human FA but in contrast to the human condition, untreated mice become moribund by 2 months of age unlike humans where the cardiac disease often does not manifest until the 3rd decade. The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress. The hearts of αMyhc mice had decreased levels of FXN and activity of mitochondrial complex II/complex IV respiratory chain. At rest, the αMyhc mice exhibited normal cardiac function as assessed by echocardiographic assessment of ejection fraction and fractional shortening, but when the heart was stressed chemically with dobutamine, αMyhc mice compared to littermate control mice had a 62% reduction in stress ejection fraction (p0.07). These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.

Read the entire article HERE

A Novel Solution-Gated Graphene Transistor Biosensor for Ultrasensitive Detection of Trinucleotide Repeats

A new way to detect GAA trinucleotide repeats (TNRs) based on a solution-gated graphene transistor (SGGT) with high performance was developed. Herein, a SGGT biosensor was constructed based on G-quadruplex DNAzymes and graphene channels. The DNAzymes quantify the captured target DNA by producing a strong catalytic current signal depending on the peroxidase-like activity. The higher the target DNA quantity captured on the gate electrode is, the higher is the concentration of DNAzymes on the surface of the gate electrode, which generates a high catalytic current. Due to the excellent self-amplifying performance of the transistor, the current signal of the SGGT is several hundreds of times larger than in conventional electrochemistry under identical detection conditions. Moreover, a large current signal can be obtained in the case of a low concentration of H2O2 when compared to the case of an enzyme-catalyzed transistor. The SGGT biosensor also exhibits an ultra-low detection limit (32.25 fM), a wide linear range (100 fM-100 nM), and excellent selectivity. The results show that the SGGT biosensor has great potential in the early diagnosis of neurodegenerative diseases.

Read the entire article HERE

New Request For Proposals: Therapeutic window of frataxin

FARA is announcing a request for proposals aimed at supporting therapeutic development in FA, by providing key preclinical data to support the development of benchmarks to improve the likelihood of success of frataxin delivery or upregulation.

Many therapeutic interventions in FA are aimed at elevating the levels of frataxin protein with small molecules or delivering frataxin to the affected tissues by means of gene, protein replacement or stem cell therapy. However, there are critical pre-clinical studies that must be done to ensure that these interventions are successful.

Applications focused on addressing one or more of the following outstanding questions will be considered:

  1. What are the levels of frataxin that are needed to restore function in cells and tissues supportive of therapeutic benefit?
  2. What is the percent of cells that need to be targeted in a tissue to achieve a clinical benefit and what is the effect of frataxin increase/delivery in a subset of cells within a tissue?
  3. What is the contribution of non cell-autonomous effects on therapeutic benefit for relevant tissues?
  4. What are the temporal aspects of frataxin increase/delivery?

Read the full RFP here.
The deadline for submission of a Letter of Intent is September 1st, 2020.
Please submit your LOI here.

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