J. Analysis of Putative Epigenetic Regulatory Elements in the FXN Genomic Locus

Fernández-Frías, I.; Pérez-Luz, S.; Díaz-Nido. Int. J. Mol. Sci. 2020, 21, 3410.

Friedreich´s ataxia (FRDA) is an autosomal recessive disease caused by an abnormally expanded Guanine-Adenine-Adenine (GAA) repeat sequence within the first intron of the frataxin gene (FXN). The molecular mechanisms associated with FRDA are still poorly understood and most studies on FXN gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of FXN transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the FXN genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.

Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia

Alexandra Clay, Kristin M. Obrochta, Russell K. Soon Jr, Christopher B. Russell & David R. Lynch; Neurol (2020). doi:10.1007/s00415-020-09868-3

Because NfL is elevated in patients, but decreases with age and disease progression, our results suggest that age is the critical determinant of NfL in FRDA (rather than clinical or genetic severity).

Therapeutic potential of stem cells for treatment of neurodegenerative diseases

Ahmadian-Moghadam, H., Sadat-Shirazi, M. & Zarrindast, M.; Biotechnol Lett (2020). doi:10.1007/s10529-020-02886-1

The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases.

CRISPR/Cas9 gene editing of hematopoietic stem cells from patients with Friedreich’s ataxia

Celine J. Rocca, Joseph N. Rainaldi, Jay Sharma, Yanmeng Shi, Joseph H. Haquang, Jens Luebeck, Prashant Mali, Stephanie Cherqui, Molecular Therapy - Methods & Clinical Development, 2020, doi:10.1016/j.omtm.2020.04.018.

Here, we report the first step towards an autologous HSPC transplantation using the CRISPR/Cas9 system for FRDA. We first identified a pair of crRNAs that efficiently removes the GAA expansions in human FRDA lymphoblasts restoring non-pathologic level of frataxin expression and normalizing mitochondrial activity. We also optimized the gene editing approach in HSPCs isolated from healthy and FRDA patients’ peripheral blood, and demonstrated normal hematopoiesis of gene-edited cells in vitro and in vivo. The procedure did not induce cellular toxic effect or major off-target events, but a p53-mediated cell proliferation delay was observed in the gene-edited cells. This study provides the foundation for the clinical translation of autologous transplantation of gene-corrected HSPCs for FRDA.

A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effects on Biomarkers of MIN-102 (Leriglitazone)

Uwe Meya, Guillem Pina, Silvia Pascual, Marc Cerrada-Gimenez, Pilar Pizcueta, Marc Martinell, David Eckland, Jeroen v.d. Wetering de Rooij
Neurology Apr 2020, 94 (15 Supplement)

Evaluation of the pharmacokinetic parameters of leriglitazone in plasma and urine after single and multiple oral administration in healthy male volunteers. Evaluation of pro-inflammatory biomarkers in plasma and CSF after oral administration of leriglitazone in healthy male volunteers.

MIN102 (Leriglitazone), a Brain Penetrant PPAR Gamma Agonist for the Treatment of Friedreich’s Ataxia (4147)

Sonia Poli, Laura Rodríguez-Pascau, Elena Britti, Joaquim Ros, Pilar González-Cab, David Lynch, Marc Martinell, Pilar Pizcueta; Neurology Apr 2020, 94 (15 Supplement) 4147;

The preclinical results support the investigation of leriglitazone for the treatment of FRDA. Leriglitazone is currently in clinical phase 2/3 for the treatment of AMN, in phase 2 for cALD and in phase 2 for Friedreich’s Ataxia.

Neurologic outcomes in Friedreich ataxia

Massimo Pandolfo, Neurol Genet Jun 2020, 6 (3) e415; DOI: 10.1212/NXG.0000000000000415

The SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials.

Making iron-sulfur cluster: structure, regulation and evolution of the bacterial ISC system

Corentin Baussier, Soufyan Fakroun, Corinne Aubert, Sarah Dubrac, Pierre Mandin, Béatrice Py, Frédéric Barras, Advances in Microbial Physiology, Academic Press, 2020, doi:10.1016/bs.ampbs.2020.01.001.

Iron sulfur (Fe-S) clusters rank among the most ancient and conserved prosthetic groups. Fe-S clusters containing proteins are present in most, if not all, organisms. Fe-S clusters containing proteins are involved in a wide range of cellular processes, from gene regulation to central metabolism, via gene expression, RNA modification or bioenergetics. Fe-S clusters are built by biogenesis machineries conserved throughout both prokaryotes and eukaryotes. We focus mostly on bacterial ISC machinery, but not exclusively, as we refer to eukaryotic ISC system when it brings significant complementary information. Besides covering the structural and regulatory aspects of Fe-S biogenesis, this review aims to highlight Fe-S biogenesis facets remaining matters of discussion, such as the role of frataxin, or the link between fatty acid metabolism and Fe-S homeostasis. Last, we discuss recent advances on strategies used by different species to make and use Fe-S clusters in changing redox environmental conditions.

Characterization of the Interruptions of the GAA Expansion and Study of Their Influence on the Severity of Friedreich's Ataxia (INTREP-AF)

ClinicalTrials.gov Identifier: NCT04346238 Posted : April 15, 2020

To date, only the partial correlation between the size of the expansion and the age of onset of Friedreich's ataxia has been established. In particular, very atypical forms of AF with a late onset (after the age of 25) are in particular explained by the low number of repetitions in the expansion, typically between 100 and 500 repetitions. However, the presence of an interruption could stabilize the size of the expansion and, therefore, be mainly associated with expansions of small sizes and therefore with a late onset of the disease.

The objective of this study is therefore to analyse and caracterize the presence and the type of interruptions of the GAA expansions in a group of patients with FA ; this data will be correlated with the age at onset of FA.

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

Julia O. Misiorek, Anna M. Schreiber, Martyna O. Urbanek-Trzeciak, Magdalena Jazurek-Ciesiołka, Lauren A. Hauser, David R. Lynch, Jill S. Napierala & Marek Napierala; Mol Neurobiol (2020). doi:10.1007/s12035-020-01899-1

Further studies confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA and protein levels. We also validated the ability of miRNA-10a-5p to bind and regulate the levels of brain-derived neurotrophic factor (BDNF), an important modulator of neuronal growth. We observed a significant decrease in the levels of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. Our comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as negative regulators of the FXN and BDNF expression, respectively. These results emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also their potential as therapeutic targets for this disease.