Saturday, September 26, 2020

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Liwei Weng, Laurent Laboureur, Qingqing Wang, Lili Guo, Peining Xu, Leah Gottlieb, David R. Lynch, Clementina Mesaros & Ian A. Blair; Sci Rep 10, 15788 (2020). doi:10.1038/s41598-020-72884-w 

Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.
Apart from our own studies on frataxin isoform E, several other studies have suggested that human mature frataxin can have an extra-mitochondria location. Alternatively, processing of the mature mouse frataxin could proceed in a different manner than in humans. If this is the case, we would suggest that mouse models do not serve as a good model for humans. Finally, as human gene therapy is tested in mouse models, it is possible that the mature human protein will undergo truncations in the mouse tissues, although they will most likely be at different sites because of the differences in amino acid sequence at the amino-terminus compared to mouse frataxin. This will impact on the assessment of efficacy and safety of the human transgene constructs (such as CAG-hFXN-HA) in mouse models.

Thursday, September 24, 2020

IXICO joins neuroimaging consortium focused on Friedreich’s Ataxia

24 Sep 2020. IXICO PLC (LON:IXI) said it has entered a five year collaboration with the Friedreich's Ataxia Research Alliance (FARA) to become a member of the TRACK-FA neuroimaging consortium, focused on exploring novel imaging markers for Friedreich’s Ataxia (FA). The company added that it will be an industry member and stakeholder in the consortium and will work alongside academic partners with expertise in neuroimaging and conducting clinical research in FA including Monash University in Australia), the University of Minnesota and Aachen University in Germany.

Wednesday, September 16, 2020

Biomarker for Friedreich's Ataxia (BioFridA) (BioFridA) Identifier: NCT04548921. Responsible Party: Centogene AG Rostock. Recruitment Status : Recruiting, First Posted : September 15, 2020 International, multicenter, observational, longitudinal monitoring study to identify biomarker/s for Friedreich's Ataxia and to explore the clinical robustness, specificity, and long-term variability of these biomarker/s Locations: Lebanon, American University of Science and Technology, Beirut, Lebanon, 16-6452 Principal Investigator: Andre Megarbane, MD

Saturday, September 12, 2020

Altered Secretome and ROS Production in Olfactory Mucosa Stem Cells Derived from Friedreich’s Ataxia Patients

Pérez-Luz, S.; Loria, F.; Katsu-Jiménez, Y.; Oberdoerfer, D.; Yang, O.-L.; Lim, F.; Muñoz-Blanco, J.L.; Díaz-Nido, J.; Int. J. Mol. Sci. 2020, 21, 6662. doi:10.3390/ijms21186662. Human olfactory ecto-mesenchymal stem cells represent a novel model that could prove useful due to their accessibility and neurogenic capacity. Here, we isolated and cultured these stem cells from Friedreich´s ataxia patients and healthy donors, characterizing their phenotype and describing disease-specific features such as reduced cell viability, impaired aconitase activity, increased ROS production and the release of cytokines involved in neuroinflammation. Importantly, we observed a positive effect on patient-derived cells, when frataxin levels were restored, confirming the utility of this in vitro model to study the disease. This model will improve our understanding of Friedreich´s ataxia pathogenesis and will help in developing rationally designed therapeutic strategies.

Friday, September 11, 2020

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana


Alejandro M. Armas, Manuel Balparda, Agustina Terenzi, Maria V. Busi, Maria A. Pagani and Diego F. Gomez-Casati; Plants 2020, 9(9), 1171, doi:10.3390/plants9091171 (registering DOI) In plants, the cysteine desulfurase (AtNFS1) and frataxin (AtFH) are involved in the formation of Fe-S groups in mitochondria, specifically, in Fe and sulfur loading onto scaffold proteins, and the subsequent formation of the mature Fe-S cluster. We found that the small mitochondrial chaperone, AtISD11, and AtFH are positive regulators for AtNFS1 activity in Arabidopsis. Moreover, when the three proteins were incubated together, a stronger attenuation of the Fenton reaction was observed compared to that observed with AtFH alone. Using pull-down assays, we found that these three proteins physically interact, and sequence alignment and docking studies showed that several amino acid residues reported as critical for the interaction of their human homologous are conserved. Our results suggest that AtFH, AtNFS1 and AtISD11 form a multiprotein complex that could be involved in different stages of the iron–sulfur cluster (ISC) pathway in plant mitochondria.

Thursday, September 10, 2020

Rare Disease Trials Require Interactions With KOLs, Patients, & Regulators


Clinical Leader, September 9, 2020; Chief Editor: Ed Miseta Minoryx Therapeutics is a small biotech hoping to bring new hope to patients suffering from orphan CNS diseases. The company of 25 employees was founded in 2011 and is seeking treatments for diseases with a high unmet medical need. The company’s leading program is leriglitazone, currently in development for multiple CNS disorders. Leriglitazone is a small-molecule selective PPAR gamma agonist. 
Another example is the company’s Friedreich’s Ataxia study, which required a different interaction with regulators. In that case, the disease was better known to physicians and Minoryx was able to locate more data on the progression of the disease. The company designed a Phase 2 trial and, upon completion of that study, will discuss the results with regulators to determine future steps.

Tuesday, September 8, 2020

Ataxia: Hope starts with measurement

The Florey Institute of Neuroscience and Mental Health. News and media. 03 Sep 2020.
The team will be developing a prototype device to measure ataxia thanks to funding received from the Biomedical Translation Bridge program administered by MTP Connect.
The $500,000 in funding was announced today by the Minister for Health, the Hon. Greg Hunt MP, with US-based advocacy organisation Friedreich Ataxia Research Alliance (FARA) confirming they will match the government’s investment.
“Whilst there are multiple treatments in development for heredity forms of ataxia in particular, without clinicians being able to make objective measurements for the condition it makes it difficult to understand the effectiveness of these. We believe that developing a device which uses sensors and sophisticated algorithms to assess ataxia progression will allow these treatments to be fast tracked,” said Associate Professor Corben.

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

Bizzoca, A.; Caracciolo, M.; Corsi, P.; Magrone, T.; Jirillo, E.; Gennarini, G.; Molecules 2020, 25, 4085. doi:10.3390/molecules25184085

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

Sunday, September 6, 2020

Registries for orphan drugs: generating evidence or marketing tools?

Carla E. M. Hollak, Sandra Sirrs, Sibren van den Berg, Vincent van der Wel, Mirjam Langeveld, Hanka Dekker, Robin Lachmann & Saco J. de Visser; Orphanet J Rare Dis 15, 235 (2020). doi:10.1186/s13023-020-01519-0

Independent disease registries for pre-and post-approval of novel treatments for rare diseases are increasingly important for healthcare professionals, patients, regulators and the pharmaceutical industry. Current registries for rare diseases to evaluate orphan drugs are mainly set up and owned by the pharmaceutical industry which leads to unacceptable conflicts of interest. To ensure independence from commercial interests, disease registries should be set up and maintained by healthcare professionals and patients. Public funding should be directed towards an early establishment of international registries for orphan diseases, ideally well before novel treatments are introduced. Regulatory bodies should insist on the use of data from independent disease registries rather than company driven, drug-oriented registries.

Saturday, September 5, 2020

Broad Institute launches new effort to study rare neuromuscular disorder

Broad Institute, NEWS / 09.3.20. By Leah Eisenstadt.
A new research and drug discovery effort at the Broad Institute of MIT and Harvard is taking aim at the rare, inherited movement disorder Friedreich’s ataxia (FA), which causes progressive damage to the nervous system. FA arises from genetic mutations that lead to dysfunction of the cell’s energy-producing organelles called mitochondria.
“The goal of the Friedreich's Ataxia Accelerator is to nucleate a small group of investigators who will bring the power of genomics to this debilitating disease,” said Mootha, who is also a Howard Hughes Medical Institute investigator and professor of medicine at Harvard Medical School and Massachusetts General Hospital.