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FARAFARA Cure FA

 

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.

 


 

Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency

FRDA has both neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the what occurs in FRDA at the cellular level in cardiomyocytes (heart cells). Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. They found that the FRDA cells had differences in the pattern of beating, and they had a deficiency in calcium handling. They defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.

Read more HERE

Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich’s Ataxia

Omaveloxolone Induced Nrf2 and Improved Mitochondrial and Neurological Function

Company Planning to Initiate Part 2 of Trial During the Second Half of 2017

Data Presentation and Conference Call Scheduled for June 2nd

 

IRVING, Texas, June 01, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) ("Reata" or "the Company"), a clinical-stage biopharmaceutical company, today announced positive data from Part 1 of the Company's Phase 2 trial (MOXIe) of omaveloxolone for the treatment of Friedreich's ataxia (FA). The trial demonstrated that in FA patients, omaveloxolone induced Nrf2, which is suppressed in FA patients, and this was associated with improvements in mitochondrial and neurological function. Dose-dependent and time-dependent effects on the modified Friedreich's Ataxia Rating Scale (mFARS) were observed at the pharmacodynamically active doses, and the maximum effect on mFARS was observed at the 160 mg dose level. The Company is planning to initiate Part 2 of MOXIe during the second half of 2017.

"We are greatly appreciative of Reata, the clinical investigators, and the study volunteers for conducting and participating in a well-designed and robust dose-escalation study. We find these results to be very exciting, and they are the ideal outcome for an early Phase 2 study. They exceed expectations in terms of safety and by demonstrating dose-dependent and clinically meaningful activity that correlated with biological activity," said Jennifer Farmer, the Executive Director of the Friedreich's Ataxia Research Alliance (FARA). "FARA and the FA community encourage urgency in advancing this program to Part 2 of the study to allow for further evaluation of efficacy and safety, as there are no approved therapies to slow progression or improve symptoms for individuals living with FA. Every day counts for our patient families."

The complete data will be presented by Dr. David Lynch, Director of the Friedreich's Ataxia Program at Children's Hospital of Philadelphia, during the afternoon of June 2, 2017 at 3:00pm EDT, after completion of the Patient-Focused Drug Development meeting hosted by FARA.

Read more HERE

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study

Friedreich ataxia is characterized by progressiveness of motor coordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear.

In this cross-sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single-finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity.

During simple finger tapping, FA patients at the lower end oft he clinical severity scale showed more activation, while those more affected by disease showed less activation in certain regions of the cerebrum. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within different regions. Greater offline motor precision was associated with less activation in the dorsal attention network.

Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia.

Read more HERE

Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathy

The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA.

A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression.

Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.

These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.

Read more HERE

Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI

Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA.

The group enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging to assess gray and white matter in specific structures. They found that both groups presented gray matter atrophy mostly in the motor cortex. They found white matter abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, they found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration and severity.

The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.

Read more HERE

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