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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.



Inducible and reversible phenotypes in a novel mouse model of Friedreich's Ataxia

Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.

Read the entire article HERE

Mitochondrial pore opening and loss of Ca2+ exchanger NCLX levels occur after frataxin depletion

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neuron survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Read the entire article HERE

The role of oxidative stress in Friedreich's ataxia

Oxidative stress and increase in the levels of free radicals are important markers associated with several pathologies, including Alzheimer's disease, cancer and diabetes. Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role.

Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia. More than twenty years later, we now know how important this protein is, being essential and part of the vital machinery which produces iron-sulfur clusters in the cell.

In this Review, we revisit the most important steps which have brought us to our current understanding of the function of frataxin and its role in disease. We discuss the current hypotheses on the role of oxidative stress in Friedreich's ataxia, reviewing some of the existing animal and cellular models. We also evaluate new techniques which can assist in the study of the disease mechanisms and in understanding the interplay between primary and secondary phenotypes.

Read the entire article HERE

Synthetic transcription elongation factors license transcription across repressive chromatin

Releasing a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes that impact human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. We present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy. Furthermore, the modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci.

Read the entire article HERE

C-Path and FARA announce collaborative data aggregation project for Friedreich’s ataxia

Tucson, AZ, and Downingtown, PA — December 4, 2017 — Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) have announced that they will work together to develop an aggregated database of clinical data for Friedreich's ataxia (FA). Use of this database will promote collaborative research to support the understanding of natural history, potential biomarkers, and potential clinical endpoints for patients with FA, which will help researchers develop more efficient clinical trial protocols to test new therapies more quickly and effectively.

"FA is a rare disease which is progressive, affects multiple organ systems, and is fatal. Treating the disease is an urgent unmet need. FA research has reached a critical juncture, where several therapies have undergone or are in clinical trials, and additional new therapies are expected to start clinical development in the next few years. The purpose of this project is to leverage and share as much information as possible, to more fully understand progression of disease, how that progression can be captured in measurable endpoints, and the effect of placebo treatment. We want to ensure that we are using all the information available to design the most efficient and robust clinical trials, giving potential therapies the best chance of success," explained Jennifer Farmer, FARA's Executive Director.

Read the entire article HERE

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