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GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients
1. Charles A. Galea ,
2. Aamira Huq ,
3. Paul J. Lockhart ,
4. Geneieve Tai ,
5. Louise A. Corben ,
6. Eppie M. Yiu ,
7. Lyle C. Gurrin ,
8. David R. Lynch ,
9. Sarah Gelbard,
10. Alexandra Durr ,
11. Francoise Pousset,
12. Michael Parkinson ,
13. Robyn Labrum,
14. Paola Giunti ,
15. Susan L. Perlman,
16. Martin B. Delatycki and
17. Marguerite V. Evans-Galea
: Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of occur in 96% affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.
: We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (i) homozygous expansions, and three compound heterozygote groups; (ii) null (no frataxin produced); (iii) moderate/strong impact, and; (iv) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses.
: Mutations in the hydrophobic core of frataxin affected stability while surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups.
: In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provides a definitive resource for investigating disease pathogenesis in FRDA.
European medical research escapes stifling privacy laws
Proposed legislation had threatened the use of genomic and clinical data in medical studies.
16 December 2015
A threat to medical research projects in Europe has been averted. European Union politicians and officials agreed on 15 December to exempt research from some of the strict provisions in planned data-protection legislation.
“This is very positive for us – the biggest threats are over,” says Michaela Mayrhofer, senior project manager at the European Union's Biobanking and Biomolecular Research Infrastructure, which is building collections of billions of biological samples across Europe and is headquartered in Vienna, Austria.
The legislation, first proposed three years ago, is primarily intended to protect people from having their digital information exploited for commercial, or other, purposes. At first medical researchers viewed the proposed rules positively because they clarified procedures for sharing clinical and genomic data across European Union (EU) member states.
1. Thiago J.R. Rezende Msc ,
2. Cynthia B. Silva MD, PhD ,
3. Clarissa L. Yassuda MD, PhD ,
4. Brunno M. Campos Msc ,
5. Anelyssa D'Abreu MD, PhD ,
6. Fernando Cendes MD, PhD ,
7. Iscia Lopes-Cendes MD PhDand
8. Marcondes C. França Jr. MD, PhD
Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia
We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons).
Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up.
Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up
Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism
Maintenance of mitochondria is achieved by several mechanisms, including the regulation of mitochondrial proteostasis. The matrix protease CLPXP, involved in protein quality control, has been implicated in ageing and disease. However, particularly due to the lack of knowledge of CLPXP’s substrate spectrum, only little is known about the pathways and mechanisms controlled by this protease. Here we report the first comprehensive identification of potential mitochondrial CLPXP in vivo interaction partners and substrates using a combination of tandem affinity purification and differential proteomics. This analysis reveals that CLPXP in the fungal ageing model Podospora anserina is mainly associated with metabolic pathways in mitochondria, e.g. components of the pyruvate dehydrogenase complex and the tricarboxylic acid cycle as well as subunits of electron transport chain complex I. These data suggest a possible function of mitochondrial CLPXP in the control and/or maintenance of energy metabolism. Since bioenergetic alterations are a common feature of neurodegenerative diseases, cancer, and ageing, our data comprise an important resource for specific studies addressing the role of CLPXP in these adverse processes.