The Friedreich's Ataxia Research Alliance (FARA) is dedicated to the pursuit of scientific research leading to treatments and a cure for
Friedreich's ataxia. FARA supports research through funding competitive grants, promoting collaboration between scientists, advocating for
public-private partnerships that support drug development and clinical research and hosting open forums for leading scientists to share their
insights, ideas and challenges to advancing treatments for FA.
FARA has provided more than 10 million in research funding over the past 10 years to scientists in both public and private organizations.
In the early years funding priorities were focused on understanding the cause of FA and the pathophysiology underlying the disease.
While there is still more to learn about the intricacies of this disease we have expanded our focus to translational and clinical research.
Principal Investigator: Dr. Gino Cortopassi
University of California, Davis
Grant made possible by funds from Ride Ataxia NorCal 2011 and The Phillip Bennett Memorial Fund.
Repurposing existing approved drugs for FRDA therapy using a novel high-throughput screening assay and a library of 1640 drugs
that have already been approved for use in humans, Dr. Cortopassi identified 40 drugs that protect FRDA patient cells from death.
The screening assay is based on the sensitivity of FRDA fibroblasts to the thiol oxidant diamide. The goal of this project is
to determine the mechanism of action of these protective drugs. Dr. Cortopassi will also examine their relative potency and their
efficacy in cell and animal models in preparation for clinical testing in humans. Because these drugs have already been approved
by the FDA for other purposes, this “repurposing” approach has substantial potential to reduce the lag time between laboratory
testing in cell and animal models and approval of the drug as a treatment for FRDA. Thus, determining the mechanism and efficacy
of these drugs is a top priority, because of the potential for rapid translation to FRDA patients.
The Kyle Bryant Translational Research Award
Principal Investigator: Dr. Joseph Sarsero
Murdoch Children’s Research Institute, Melbourne, Australia
Correction of FRDA iPS cells by non-viral gene therapy.
FRDA is an inherited progressive disorder of the nervous system and muscles that results in the inability to coordinate voluntary
muscle movements. Improper heart function is also a common and life-threatening condition of the disease. The genetic defect that
causes FRDA results in reduced levels of an essential protein termed frataxin in all cells of the body. Stem cell therapy has the
potential to repair or replace damaged tissues and restore organ function in individuals with FRDA. Major advances in stem cell
technologies have led to the development of ‘embryoniclike cells’ from adult human tissue. These cells, known as induced-pluripotent
stem (iPS) cells, have essentially the same properties as embryonic stem cells, and thus can be used to derive any mature cell type.
Prior to the transplantation of nerves or heart cells derived from FRDA iPS cells, it will be necessary to restore frataxin protein
to levels compatible with normal cell function. In this project Dr. Sarsero and his collaborator, Dr. Mirella Dottori, propose a
means to correct the defect inherent in FRDA iPS cells by a gene therapy approach that will restore normal FRDA gene expression and
does not leave any ‘genetic scars’ in the cells. The strategy addresses major safety concerns for the clinical use of iPS cells and
should facilitate compliance with regulatory agency requirements for the approval of the use these cells in transplantation medicine.
The 2010 Kyle Bryant Translational Research Award was given to:
Dr. Devin Oglesbee - Mayo Clinic, Project title: High-Throughput Meso-Scale Discovery of Frataxin Enhancer
Dr. Martin Delatycki - University of Melbourne, Project title: An open label proof of principle study of resveratrol
as a treatment for Friedreich’s ataxia
Resveratrol is not a new compound but new to FA.
Resveratrol is found in the skin of red grapes. Resveratrol has been under intense investigation as a compound that
could improve mitochondrial function and some studies suggest increased longevity, lowering glucose levels and anti-cancer activity.
Researchers in Australia found that resveratrol also increased frataxin levels in laboratory studies.
Through the Kyle Bryant Translational Research Award, FARA has funded an open-label, pilot study of Resveratrol at the
University of Melbourne which began in April 2011 and should be completed in the first half of 2012.
Under Dr. Cortopassi, UC Davis: Dr. Cortopassi and his team screened 1600 drugs already approved for use in humans,
and have identified 40 which protect the Friedreich’s ataxia patient cells from death. Their goals are to determine
the mechanism of action of the drugs, relative potency, and efficacy in cell and animal models in preparation for clinical
testing in humans. The continuation of this study has been funded by the Phillip Bennett Translational Research Award.
The 2009 Kyle Bryant Translational Research Award was given to:
Dr. Marek Napierala - University of Texas, MD Anderson Cancer Center
Project Title: Crosstalk between microRNAs and iron metabolism in pathogenesis of Friedreich's ataxia.
This award made possible by a sponsorship made by Outback Steakhouse.
MicroRNAs are small RNA molecules important for regulating translation of genes to proteins.
The aims accomplished in this study included: establishing the miRNA signature in Friedreich’s ataxia and to identify
miRNA target transcripts involved in iron homeostasis and to defining the effects of frataxin deficiency and iron
imbalance on expression of genes involved in miRNA processing. Specifically, 8 miRNAs were found to be differentially
expressed between the FRDA and the control cells. These studies allowed us to define FRDA-specific miRNA biomarkers and
to uncover their potential targets. These miRNAs participate in controlling of the expression of 7 genes important in
iron metabolism. Along with this work this group has also established a bank of human induced pluripotent stem cells
(iPSCs) which includes control cell lines and 5 clones of FRDA iPSCs. The FRDA cell lines are reprogrammed patient
fibroblasts GM04078 from Coriell repository harboring 340 and 420 GAA repeats and GM03665 containing 560 and 860 GAAs.
These iPSCs were then further differentiated in to neurons so that they could be used further study the miRNA expression
and in the future these cell lines can be used for other studies including the evaluation of therapeutic drug targets.
Dr. Mark Payne - Indiana University School of Medicine
TAT Frataxin: Dr. Mark Payne, who first described the possibility of frataxin replacement therapy via TAT-Frataxin
has been developing this exciting prospect for FA therapy, He makes synthetic frataxin protein and uses a unique delivery system
(a protein fragment called a Trans-Activator of Transcription or TAT) to get the frataxin protein to the mitochondria. Dr. Payne
has tested TAT-frataxin in the FA mice and demonstrated proof of principle and compelling results (see publication -
http://hmg.oxfordjournals.org/content/early/2011/11/23/hmg.ddr554.abstract?ct=ct ). Dr. Payne’s approach increases the life span
and weight of FA mice and improves their cardiac function. Dr. Payne is looking to develop this approach further and, with FARA’s assistance,
is seeking a pharmaceutical partner to help do so.
Dr. Gino Cortopassi - University of California Davis, Project Title: Screening for mitofunctional Friedreich's ataxia therapeutics.
The 2008 Kyle Bryant Translational Research Award was given to:
Dr. James Rusche - Repligen Corporation
HDAC inhibitors are a class of compounds that interfere with the histone deactylase that functions
to keep the DNA of a gene tightly coiled so as to silence that gene’s expression of its protein. Dr. Joel Gottesfeld of
The Scripps Research Institute in La Jolla, California first described the potential use of these compounds in FA to overcome
the gene silencing effect of the predominant genetic mutation that causes FA. Dr. Gottesfeld and RepliGen are working together
to design novel HDAC inhibitors that act at the DNA/gene level and increase frataxin protein production in cells from FA patients
and in FA animal models. The Repligen Corporation has licensed these HDAC inhibitors from Scripps for the purposes of advancing
them through preclinical development and clinical trials in FA. Repligen and Dr. Gottesfeld are working very closely together,
with support from FARA, MDA and GoFAR, and with the FA mouse-model investigators so as to develop the very best HDAC inhibitor for FA.
RepliGen has identified a lead candidate (RG2933) and has filed an IND with the FDA in the United States to begin testing these
compounds in humans. The FDA has requested additional toxicology studies which are scheduled for completion in 2011.
RepliGen has also made similar request of the European regulatory agency and they were given permission to advance Phase I studies
in Europe. Repligen hopes to begin Phase I safety studies in 2011 in Europe (Italy). While work continues on pre-clincal and safety
studies of RG2833, RepliGen has also done moved forward with identifying another HDAC inhibitor, a follow-on compound, that they
have begun pre-clinical studies in as well. The follow-on compound may offer some advantages over RG2833 in terms of metabolic
stability and brain penetration. A recent review article discussing the development of these compounds -
Drs. Subha V. Raman and Roula al-Dahhak - Ohio State University, Project Title: Preclinical Markers of Cardiomyopathy
in Friedreich's ataxia
The 2007 Kyle Bryant Translational Research Award was given to: