Programs: Research & grant program: fara's commitment to funding high quality research projects that move us closer to effective treatments continued at an accelerated pace in 2014. In total, fara provided >$4m in basic and translational and clinical research grants, a new friedreich's ataxia center of excellence, scientific conference support and clinical research infrastructure funding. Over the past year, >35 new letters of intent for funding requests were submitted, 21 full applications were submitted and after rigorous peer review, 15 were determined meritorious and awarded funding in 2014 and early 2015. In addition, based on excellent progress, continuation funding was provided for 14 projects, for a total of 29 research grants awarded. Fara also awarded two conference grants to support scientific meetings with content focused on friedreich's ataxia. These funded projects address numerous important research questions that directly target fara's strategic research initiatives, including evaluating of mechanisms of disease, drug discovery, pre-clinical and clinical studies of lead candidates in the treatment pipeline, advances in gene and cell therapy approaches, advances in differentiation of induced pluripotent stem (ips) cell lines from fa patients into sensory neurons and cardiomyocytes, development of new animal models, cardiac research and evaluation of novel biomarkers. Several are co-funded with our friedreich's ataxia advocacy group partners; this collaborative approach both increases the number of available research dollars and helps to minimize duplication of effort. Of note, fa shares similar symptoms and disease mechanisms with other diseases, both rare and common. Research into fa is providing insights and advances in other diseases such as mitochondrial diseases, muscular dystrophies, diabetes, and cardiomyopathy. New in 2014 - friedreich's ataxia center of excellence, philadelphia pain march, fara announced the establishment of the penn medicine/ children's hospital of philadelphia friedreich's ataxia center of excellence. The center was launched with a gift of $3. 25 million (over 3 years) presented by fara in partnership with the hamilton and finneran families. This center will help to expedite basic science and drug discovery findings for new treatments, provide resources for clinical research and care that will help to increase understanding of the disease, and improve outcomes for individuals living with friedreich's ataxia. Projects and investigators being funded include dr. Rob wilson- drug discovery, dr. David lynch- clinical and neuroscience research, dr, ian blair- metabolic biomarkers, and dr. Kim lin- cardiac research. A few highlighted new research grants:2014 keith michael andrus memorial award (for cardiac research), title: identification of therapeutic compounds on a cardiac drosophila model of friedreich's ataxia, principal investigator, dr. Veronique monnier (unversite' paris)dr. Veronique monnier and her team have developed a drosophila cardiac model of friedreich's ataxia that recapitulates the defects of cardiac function observed in patients and frda mouse models, in particular heart dilatation and impaired systolic function. In a recent publication describing this frda fly model, they showed that methylene blue, a clinically approved drug, was able to prevent the heart dysfunction (tricoire h, palandri a, bourdais a, camadro jm, monnier v. Human molecular genetics 23:968- 979, 2014). The major goal of this project is to use the drosophila cardiac model to identify new therapeutic compounds through a medium-scale unbiased drug screening of 1280 compounds. Cardiac imaging will be performed in vivo to select compounds that improve the heart function of the fly. This drug screen has great potential for identifying novel compounds that are likely to lead to therapeutic interventions for frda. 2014 kyle bryant translational research award, title: small molecule induced exon skipping of mlh3 to slow repeat expansion in an frda mousel model, principal investigator, dr. Edward grabczyk, lousiana state university. Dr. Grabczyk found that a protein called msh3 causes gaa repeats in the fxn gene to expand. He then discovered that transcription through the repeat and the sequential actions of several dna mismatch repair proteins called mutsbeta (msh2/msh3 heterodimer) and then mutlgamma (mlh1/mlh3 heterodimer) are linked to cell loss or repeat expansion in frda patient tissue samples. Mutlgamma is the protein complex that cuts the dna in the repeat to start the expansion. Without the cut, there is no expansion. When treating cells with splice-switching oligonucleotides (ssos), the repeat stops expanding. Dr. Grabczyk will explore and test the use ssos to block this expansion in mouse models of fa as a first step heading to human trials. Title: activation of frataxin expression by duplex rna, principal investigator, dr. David corey,(ut southwestern dr. David corey designed duplex rnas to recognize the repeat region in fa and potentially interfere with chromatin contacts that might contribute to decreased transcription. He has discovered that introduction of these duplex rnas into fa-patient derived cells caused an increase of fxn mrna and protein to levels similar to those in normal cells. These data suggest that duplex rnas can be used to up-regulate fxn expression and may provide a new strategy for therapy. Title: early and longitudinal assessment of neurodegeneration in the brain and spinal cord in friedreich's ataxia co-principal investigators: pierre-gilles henry and christophe lenglet (university of minnesota) the overall goal of this project is to demonstrate the feasibility of identifying and tracking structural and neurochemical changes in the spinal cord and brain of patients with frda, especially at an early stage of the disease. Drs. Henry and lenglet will use both magnetic resonance spectroscopy and diffusion magnetic resonance imaging, which provide complementary information on neurochemical and microstructural changes. These studies may result in novel and unique tools for the quantitative assessment of disease progression and treatment efficacy in prospective therapeutic trials of frda. Additionally, fara continues to support of the development of new mouse models of fa with research funding the jackson laboratories, bar harbor, maine and dr. Vijay chandran at the univeristy of california los angeles. Results reported from fara awarded grants - in 2014, there were >20 medical and scientific publications that were detailed reports of fara funded research. Here are two highlighted publications:dr. Helene puccio a research director at the french institute of health and medical research (inserm) and fara funded scientist, has been testing a gene-therapy approach in the cardiac fa mouse model that she developed in her lab at the institute de genetique moleculaire et cellulaire. The results show that a single intravenous injection of aavrh10 expressing frataxin is not only capable of preventing the development of heart disease in the mouse, but also, fully and rapidly treats the mice with advanced stages of heart disease, returning the heart to normal function. The results of this research were fully reported in nature medicine, april 2014. Fara has continued to fund both cardiac and neuronal gene therapy research in dr. Puccio's laboratory. Dr. David lynch, at the children's hospital of philadelphia, completed in 2103 and 2014 a small pilot phase 2a of study interferon gamma in children with fa, with funding from fara and support from vidara (now horizon pharma) which donated the drug for the initial study. The primary purpose was to evaluate safety and tolerability of interferon gamma and to see if there was an increase in frataxin levels. The full results were presented at the chop fa symposium and published in acta neurologica scandivanica in october 2014. In summary, while there was no significant change in frataxin levels across the group, individual data in certain tissues (buccal cells) displays a lot of "noise" - levels spiking up and down, which is something that does not normally occur. More intriguing, the clinical data obtained from the study showed a significant improvement in neurological function measured by the friedreich ataxia rating scale (fars). It is important to note that this study did not have a control or placebo group. . These results are supportive of the need for further investigation. Horizon pharma, the company that sells actimmune (interferon gamma) in the united states, is committed to moving forward. They are presently in planning stages of what we hope will be a definitive phase 3 study (placebo controlled in a much larger group of individuals with fa).
research conferences: fara organizes and supports a number of scientific conferences to improve sharing of knowledge, insights and advances and build collaborations and synergistic connections between fa researchers. May 2014 - fara and gofar (italian fa advocacy organization) co-hosted a meeting on friedreich's ataxia mouse models in philadelphia. Academic and biopharmaceutical scientists made up the 50 participants in the meeting. New mouse models in development were presented by m. Pook and v. Chandran (fara grantees). Further characterization of mitochondrial dysfunction and neurodegeneration existing models was highlighted by research from j. Magrene and c. Lutz (fara grantees). C. Lutz from the jackson laboratories also led a discussion on further mouse model development work needed to full gaps so that models with more robust and disease relevant phenotype would be available for drug development. After the meeting fara and gofar awarded funds to jackson laboratories to begin new model development. October 2014 - fara organized a meeting hosted at the national institutes of health on all aspects of biomarker exploration in fa and their importance to advancing treatments. Scientists, government officials and pharmaceutical representatives made up the 60 participants in the meeting. A biomarker consortium was created out of the meeting to help take identified projects/ needs forward. In 2014, fara began planning the next fa international scientific conference. Fara decided to partner with other international ataxia research organizations to combine efforts and conference needs. The 2015 international ataxia research conference will be in windsor, england, march 25-28, 2015. Fara is co-organizing and hosting the meeting with ataxia uk, ataxia ireland and gofar. Conference steering committee was established in early 2014, preliminary program and invited speakers were confirmed and registration and scientific abstracts opened in july 2014. At the end of 2014 there were >150 abstracts submitted and >250 confirmed delegates including representatives from the european medical association. The conference program can be found at http://www. Curefa. Org/conference. Html
education, awareness & outreach programs: friedreich's ataxia (fa) is a rare disease; affecting 1 in 50,000 individuals. Fara is dedicated to raising awareness for fa. Fara has utilized both traditional and social media strategies to bring greater awareness to fa in the general public and to engage and educate the fa community. For example, fara conducted a social media campaign that encouraged community participation leading up to rare disease day and fa awareness day. Fara also hosted webinars to inform the community about the latest developments in fa research and some of the results of funded grants. Fara co-organized two patient symposiums with clinical research network sites, children's hospital of philadelphia (chop) and university of south florida (usf). The chop and fara team led an all-day symposium at in king of prussia, pa on october 13th, 2014. There were more than 175 patient families who participated. The symposium provided:" clinical updates, including cardiology and neurology, in patients with fa;" updates on current research and clinical trials, including gene therapy, interferon gamma, rna based approaches to unsilencing the geneand" panel discussion on home modifications to improve accessibility. The symposium at usf was held on sept 4, 2014 had about 200 attend and was streamed live on facebook and there were several hundred more views. The usf symposium featured a distinguished research panel providing updates on understanding how and why the gene mutations leads to decreased frataxin and specific therapeutic approaches including, hdac inhibitors, advances in gene therapy. The patient panel discussion shared experiences related to participation in clinical trials and research. The fara ambassador program which was launched in 2011 with >20 participants had a year of growth and transformation in 2014. The mission of the fara ambassadors is to be positive, supportive, peer representatives for the fa community; actively raising awareness and funds for fara. In 2014, fara facilitated formal training for the ambassador leadership team and ambassadors. The ambassador blog project team consists of three admins and 6 more team members. In 2014, they achieved >100 posts with ~40,000 views. The ambassadors also started a card program in which they designed cards to send to the various stakeholders and community members throughout the year to say thank you or to offer encouragement. They are averaging about 20 cards per month. Finally, the ambassadors have done important outreach in visiting >8 academic laboratories and biopharmaceutical companies to provide the patient perspective of fa, and sharing their personal experiences at fa symposia.
