FARA's Mission is to marshal and focus the resources and relationships needed to cure FA by raising funds for research, promoting public awareness, and aligning scientists, patients, clinicians, government agencies, pharmaceutical companies and other organizations dedicated to curing FA and related diseases.
This group used magnetoencephalography to investigate the developmental vs progressive character of the impairment of spinocortical proprioceptive pathways in Friedreich ataxia (FRDA). Neuromagnetic signals were recorded from 16 right-handed patients with FRDA (9 female patients, mean age 27 years, mean Scale for the Assessment and Rating Of ataxia [SARA] score 22.25) and matched healthy controls while they performed right finger movements either actively or passively. The coupling between movement kinematics (i.e., acceleration) and neuromagnetic signals was assessed by the use of coherence at sensor and source levels. Such coupling, that is, the corticokinematic coherence (CKC), specifically indexes proprioceptive afferent inputs to the contralateral primary sensorimotor (cSM1) cortex. Nonparametric permutations and Spearman rank correlation test were used for statistics. In both groups of participants and movement conditions, significant coupling peaked at the cSM1 cortex. Coherence levels were 70% to 75% lower in patients with FRDA than in healthy controls in both movement conditions. In patients with FRDA, coherence levels correlated with genotype alteration (i.e., the size of GAA1 triplet expansion) and the age at symptom onset but not with disease duration or SARA score. This study provides electrophysiologic evidence demonstrating that proprioceptive impairment in FRDA is mostly genetically determined and scarcely progressive after symptom onset. It also positions CKC as a potential biomarker of proprioceptive impairment in FRDA.
This group assessed the effect of methylprednisolone on safety, tolerability and ability in Friedreich Ataxia (FRDA). The study was an open-label trial of pulse methylprednisolone on 11 participants with FRDA. All participants followed a 28-day treatment cycle, repeated 7 times. Patients were assessed with the timed 25 foot walk (T25FW), 1-minute walk (1MW), the Friedreich Ataxia Rating Scale (FARS), and 9-Hole Peg Test (9HPT). Efficacy was tested by comparing baseline and week 26 visits, separated into adult and pediatric groups. In comparisons of participants' baseline and week 26 visits, only the pediatric cohort's 1MW score showed change (p
Chemically reinforced essential fatty acids (FAs) promise to fight numerous age-related diseases including Alzheimer's, Friedreich's ataxia and other neurological conditions. The reinforcement is achieved by substituting the atoms of hydrogen with the isotope deuterium. This substitution leads to a significantly slower oxidation, inhibiting membrane damage. The approach has the advantage of preventing the harmful accumulation of reactive oxygen species (ROS) by inhibiting the propagation of lipid peroxidation while antioxidants potentially neutralize beneficial oxidative species. Here, we developed a model system to mimic the human dietary requirement of omega-3 in a worm model to study the role of deuterated polyunsaturated fatty acids (D-PUFAs). Deuterated trilinolenin [D-TG(54:9)] was sufficient to prevent the accumulation of lipid peroxides and to reduce the accumulation or ROS. Moreover, D-TG(54:9) significantly extended the lifespan of worms under normal and oxidative stress conditions. These findings demonstrate that D-PUFAs can be used as a food supplement to decelerate the aging process, resulting in extended lifespan.
This group used magnetoencephalography (MEG) to study the spatio-temporal dynamics of responses involved in sensory processing in the neocortex, and the identify any early changes that might occur in FA. They looked at tactile (TERs) and auditory (AERs) evoked responses and early neocortical change detection responses indexed by the mismatch negativity (MMN) in sixteen FRDA patients and matched healthy subjects. They looked for correlations between the maximal amplitude of each response, genotype and clinical parameters. They found that evoked responses were detectable in all FRDA patients but one. In patients, TERs were delayed and reduced in amplitude, while AERs were only delayed. Only tactile MMN responses at the contralateral secondary somatosensory cortex were altered in FRDA patients. Maximal amplitudes of TERs, AERs and tactile MMN correlated with genotype, but did not correlate with clinical parameters. The authors conclude that in FRDA, the amplitude of tactile MMN responses are reduced and correlate with the genotype, while auditory MMN responses are not altered.
Young investigators are invited to present posters at the 12th Annual Friedreich’s Ataxia Symposium hosted by The Children’s Hospital of Philadelphia (CHOP) and FARA at a welcome reception on the evening of Sunday, October 13, and throughout the day on Monday, October 14, 2018 at the Crowne Plaza Valley Forge in King of Prussia, PA. This symposium presents an opportunity to share your work not only with colleagues but also with the patient community. Priority will be given to those who can best present to a lay audience. Deadline for submissions: July 15th, 2019.
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocytes getting bigger, death of muscle fibers, and inflammatory infiltration, heart tissues show fibrosis and disorganized capillaries. This group examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69. They quantified the numbers of capillaries for comparison with the number of cardiac cells in the same field. The median ratio of capillaries to cardiomyocytes in samples from unaffected individuals was 1.0. In FA, the number of cardiomyocytes/mm² was significantly less, and the median ratio of capillaries to heart fibers was 2.0. There was a significant correlation of the expanded guanine-adenine-adenine trinucleotides (shorter allele, GAA1) with a younger age of onset, shorter disease duration, and lower cardiomyocyte counts. The ratio of capillaries to heart fibers was higher in patients with long GAA1 repeat expansions. Data supports endothelial-to-mesenchymal transition in the pathogenesis of cardiac fibrosis in FA. We propose that the pathogenesis of FA heart disease includes primary fibrosis.
Expansions of trinucleotide repeats are associated with genetic disorders such as Friedreich's ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. p53 protein recognizes specific structures in the DNA, dependent on sequence and structure. The focus of this work was analysis of the p53 structure-selective recognition of repeat sequences associated with human neurodegenerative diseases. The group studied how p53 and several deletion variants bound to repeat sequences folded into different shapes that occur in cells. They show that p53 binds to all studied DNA structures that are not the standard helical structure (non-B DNA structure), with a preference for structures formed by pyrimidine rich strands. They found a specific part of p53 to be crucial for recognition of such non-B DNA structures. They also observed that p53 prefers binding to the Pyrimidine-rich strand over the purine rich strand in non-B DNA from the repeat sequence in the first intron of the frataxin gene. The binding of p53 to this region was confirmed in human Friedreich's ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to non-B DNA structures in trinucleotide repeat sequences.
High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. This group demonstrates that DMF significantly increases frataxin gene (FXN) expression in FA cell models, FA mouse models and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell models. In FA patient cells, they demonstrate that DMF significantly increases initiation of new FXN transcripts and reduction in DNA structures thought to slow FXN production, significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. As deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, with further work DMF could be a possible therapy for FA.
Oligonucleotide drugs are experiencing greater success in the clinic, encouraging the initiation of new projects. Resources are insufficient to develop every potentially important project and persuasive experimental data using cell lines close to disease target tissue is needed to prioritize candidates. This group has previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived cells. They further tested these compounds in patient derived cells formed into cells that develop into neurons (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC's cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using previous cell types. Oligonucleotides with various chemical modifications were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. This data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.
Omaveloxolone is a potential therapy thatactivates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich's ataxia. This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich's ataxia patients. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich's ataxia patient PK profile. The authors found that oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measurable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes was also observed. Clinically, oral administration of omaveloxolone to Friedreich's ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.