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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.



Minoryx Therapeutics completes enrollment in FRAMES phase 2 trial with leriglitazone in Friedreich's Ataxia

Recruitment of 39 patients in multicenter European phase 2 trial completed ahead of schedule – Minoryx Therapeutics, a company specializing in the development of innovative treatments for orphan central nervous system (CNS) diseases, today announces that it has completed recruitment in the FRAMES phase 2 clinical trial of its novel PPARγ agonist, leriglitazone (MIN-102), in patients with Friedreich's Ataxia.

FRAMES is a multicenter, randomized, double-blind, placebo-controlled trial that will assess the efficacy and safety of leriglitazone in patients with Friedreich's Ataxia. Recruitment of 39 patients in four European countries was completed in just four and a half months, well ahead of schedule.

Read the entire Press Release HERE

Health-related quality of life and depressive symptoms in Friedreich ataxia

The aim of the present study was to assess FRDA patients' perception of HRQOL and to determine the influence of depression, and demographic and clinical variables. The sample consisted of 62 patients with genetically confirmed FRDA. The SF-36 Health Survey was used to assess HRQOL. Depressive symptoms were evaluated with the Beck Depression Inventory-II. FRDA patients' mean scores were significantly lower than the values for the Spanish population in all SF36 dimensions. Average z scores ranged from - 5.5 in physical functioning to - 0.48 in mental health. Age and clinical variables were significant predictors of HRQOL in only several dimensions, whereas BDI scores were able to predict a significant percentage of variance in all SF36 dimensions, except physical functioning. This study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.

Read the entire article HERE

Unique roles of iron and zinc binding to the yeast Fe-S cluster scaffold assembly protein "Isu1"

Mitochondrial Fe-S cluster biosynthesis is accomplished within yeast utilizing the biophysical attributes of the "Isu1" scaffold assembly protein. During assembly, the scaffold helps direct the delivery and utilization of Fe(ii) and persulfide substrates to produce [2Fe-2S] clusters, however Zn(ii) binding alters the activity of the scaffold while at the same time stabilizes the protein in its structured state. Understanding the interplay between Fe(ii) and Zn(ii) binding to Isu1 in vitro may help clarify metal loading events that occur during Fe-S cluster assembly in vivo. The authors determine the metal : protein stoichiometry for Isu1 Zn and Fe binding to be 1 : 1 and 2 : 1, respectively. As expected, while Zn binding shifts the Isu1 to its structured state, folding is not influenced by Fe(ii) binding. X-ray absorption spectroscopy (XAS) confirms Zn(ii) binds to the scaffold's cysteine rich active site but Fe(ii) binds at a location distinct from the active site. XAS results show Isu1 binding initially of either Fe(ii) or Zn(ii) does not significantly perturb the metal site structure of alternate metal. XAS confirmed that four scaffold orthologs bind iron as high-spin Fe(ii) at a site composed of ca. 6 oxygen and nitrogen nearest neighbor ligands. Also, Zn binding dramatically reduces the Fe-S cluster assembly activity of Isu1 even in the presence of frataxin. Given the Fe-binding activity reported for Isu1 and its orthologs here, a possible mechanism involving Fe(ii) transport to the scaffold's active site during cluster assembly has been considered.

Read the entire article HERE

Mechanism of activation of the human cysteine desulfurase complex by frataxin

The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to Friedreich's ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. Although previous studies show that FXN stimulates the activity of this assembly complex, the mechanism of FXN activation is poorly understood. In this study, a radiolabeling assay and stopped-flow kinetics are used to establish that FXN is functionally linked to the mobile S-transfer loop cysteine of NFS1. The results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. The authors propose an architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.

Read the entire article HERE

Two new Pfizer-coauthored studies validate Novoheart’s pioneering human bioengineered heart tissues and chambers for improving drug development

Published in the July 2019 issue of Stem Cell Research and Therapy2, Novoheart developed the world's first customized, 3D engineered, human cardiac tissue models of Friedreich's ataxia (FRDA), a rare neuromuscular degenerative disease that affects over 1 in 50,000 people worldwide. FRDA patients have a defective Frataxin gene, which often leads to lethal heart complications. This new disease model, based on MyHeartTM assays, was created using genetically modified as well as FRDA patient-derived cells, capturing both electrical and mechanical defects of the heart observed in FRDA patients.

This new approach marks an important step away from using animals as traditional testing models – they have limited predictive ability for drug discovery due to dramatic differences from human physiology. Novoheart's FRDA models, on the other hand, offer an innovative and powerful human-based platform to develop new therapies for FRDA's cardiac symptoms, for which no effective treatments are currently available.

With sole ownership of the intellectual property rights, Novoheart is now commercializing the FRDA disease model and has subsequently confirmed commercial contracts with multiple drug developers.

Read the Press Release HERE

Read the article HERE

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