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FARA Funded Research

Your generous support has funded all the research listed below.

For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.



Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron-sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. For instance, FXN mRNA and protein levels as well as FXN GAA-repeat tract lengths are routinely determined using all of these cell types. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Herein, we conducted unbiased RNA sequencing to profile the transcriptomes of fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Bioinformatic analyses revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins in FRDA fibroblasts. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in FRDA fibroblasts. Finally, comparison of genes differentially expressed in FRDA fibroblasts to three previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease. When performed on statistically meaningful sample group sizes, unbiased global profiling analyses utilizing peripheral tissues are critical for the discovery and validation of FRDA disease biomarkers.

Read the entire article HERE

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

Read the entire article HERE

Can rehabilitation improve the health and well-being in Friedreich's ataxia: a randomized controlled trial?

OBJECTIVE: To determine the effectiveness of a six-week rehabilitation programme followed by a home exercise programme for Friedreich's ataxia.

DESIGN: Randomized, delayed-start control single-blind trial.

SETTING: Outpatient rehabilitation centre.

SUBJECTS: Ambulant or non-ambulant individuals with Friedreich's ataxia.

INTERVENTION: Participants were randomized to a six-week outpatient rehabilitation programme, immediately (intervention group) or after a six-week delayed-start (control group). The rehabilitation was followed by a six-week home exercise programme.

MAIN MEASURES: The primary outcome was the Functional Independence Measure. Other measures included the Friedreich Ataxia Impact Scale and the Friedreich Ataxia Rating Scale. Outcomes were administered at baseline, 6, 12 and 18 weeks.

RESULTS: Of 159 individuals screened, 92 were excluded and 48 declined to participate. A total of 19 participants were enrolled in the study. There was no significant difference in Functional Independence Measure change from baseline to six weeks in the intervention group (mean ± standard deviation, 2.00 ± 3.16) as compared to the control group (0.56 ± 4.06). Change in the Friedreich Ataxia Impact Scale body movement subscale indicated a significant improvement in health and well-being in the intervention group compared to the control group ( P = 0.003). Significant within-group improvements in the Friedreich Ataxia Impact Scale and the motor domain of the Functional Independence Measure post-rehabilitation were not sustained post-home exercise programme.

CONCLUSION: Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich's ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Read the entire article HERE

CRISPR Therapeutics Awarded Grant from FARA to Collaborate with University of Alabama at Birmingham on Gene-edited Treatments for Friedreich’s Ataxia

ZUG, Switzerland and CAMBRIDGE, Mass., Oct. 13, 2017 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (NASDAQ:CRSP), a genome editing company focused on creating transformative medicine for serious diseases, today announced the receipt of the Kyle Bryant Translational Research Award from Friedreich’s Ataxia Research Alliance (FARA), a non-profit organization that is focused on curing Friedreich’s Ataxia (FA). The grant is awarded to fund research on in vivo CRISPR/Cas9-based gene-editing approaches to treat FA, which will be performed in collaboration with Dr. Marek Napierala at University of Alabama at Birmingham. This announcement coincides with FARA’s rideATAXIA Philadelphia event, a lead location in an annual bike ride program founded by patient Kyle Bryant, that increases FA awareness and raises funds to treat and cure FA through research.

Read the full Press Release HERE

IARC 2017 Follow Up

The FARA Team returned from the four-day International Ataxia Research Conference (IARC) in Pisa, Italy a bit jet-lagged but buzzing with energy that results from the sharing of good research results. IARC2017 was co-organized by goFAR, Ataxia UK and FARA and simply by the numbers included:

  • over 400 attendees- researchers, clinicians, patients, and government, regulatory, and industry representatives.
  • Representatives from 22 countries
  • >15 pharma/ biotech companies
  • >30 platform presentations on FA
  • Over 95 poster presentations on FA!!!

In addition to the impressive engagement numbers, the IARC had many meaningful research and collaboration take-aways such as:

Young Investigators
The IARC2017 welcomed an increasing number of young investigators, demonstrating growing interest in research for the ataxias. The host organizations believe in developing and mentoring the next generation of researchers and were honored to give nine scholarships to graduate students and post-doctoral fellows who submitted competitive abstracts. In order to help these young investigators make contacts in the field and develop their careers in ataxia research, FARA provided a lunch at the start of the meeting to help young investigators meet more senior investigators and learn about options for career development within the field. In addition, among more than 50 competitive Young Investigator Posters, Nesli Ece Sen and Saba Saqlain earned honors for best Young Investigator Posters for their work in ataxia and Friedreich’s ataxia respectively.

International Collaboration
Ataxia is not just a US or a European disease. It is a global disease, requiring international collaboration on all fronts. These collaborations are the power behind research advancement and treatments for FA. The research advocacy organizations held a meeting at IARC2017 and discussed the importance of the FA Global Patient Registry as an essential resource for both clinical trial readiness and advancing research. The partner organizations committed to further collaboration in expanding and growing the patient registry.

Exercise is Good
Several researchers presented data on the benefits of exercise for people living with FA. Dr. Zen Yan from University of Virginia presented data in mice showing that long term aerobic exercise is seen to slow FA onset (Click here for more information) Dr. Sarah Milne from Monash University in Australia also presented a poster demonstrating that physical rehabilitation improved physical and emotional health. There were also several other poster and platform presentations drawing attention to the need to treat symptoms of visual dysfunction, hearing loss, speech and swallowing and depression.

Patient & Clinical Trial Design Roundtables
Individuals with ataxia and parents and caregivers joined the meeting for a special patient roundtable discussion to share their personal stories and need for treatment. This roundtable made clear statements about the need to not only focus on stopping and curing the disease, but also asserted that treatments which target symptoms are meaningful. If therapies could improve symptoms such as vision and hearing loss or speech impairment, this would be significant for people living with ataxia. (Click here for more information) There was also informative roundtable on clinical trial design for ataxias that featured representation from the European Medical Association, ataxia patient community, clinical neurologists and pharmaceutical companies. This allowed for important discussion among all stakeholders on good clinical trial design. Some themes that arose from this discussion included the need for better communication between study sponsors and study participants and the need for objective outcome measures.

Advancing Therapies
The conference included more than 20 platform and poster presentations focused on drug discovery, preclinical and clinical outcomes in FA. These presentations demonstrated progress in many aspects of the treatment pipeline. Encouraging results of recent clinical trials were reported including Reata's Phase 2 MOXIe study, as well as a number of talks on new therapeutic options that may reach the clinic soon. There has been significant growth and advancement in drug discovery and development for therapies that target frataxin (ie the root cause of FA). This was most notable in the number of presentations on genetic based therapies including oligonucleotide and gene replacement strategies. To read more about some of the research presented at the conference, click one of the links below:

Thank you to all who made IARC2017 a success- the host organization- goFAR, steering committee, presenters, and participants. You’ve shown once again that Together We Will Cure FA!
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