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.

A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals With Friedreich Ataxia (TRACK-FA) ((TRACK-FA))

ClinicalTrials.gov Identifier: NCT04349514. Estimated Study Start Date :June 2020

The aim of TRACK-FA is to develop an FA neuroimaging dataset from brain and spinal cord that is suitable for assessing the potential value of neuroimaging biomarkers and providing a basis for instituting them in clinical trials. The dataset will comprise a range of neuroimaging measures to assess changes in spinal cord and brain regions that have previously shown to be compromised in individuals with FA. In addition to neuroimaging measures, TRACK-FA will also include clinical, cognitive data and biospecimen data. The TRACK-FA dataset will provide a unique opportunity for academic researchers in collaboration with industry partners to access the images, subsidiary data, and associated clinical data for community research.

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

Espinós, C.; Galindo, M.I.; García-Gimeno, M.A.; Ibáñez-Cabellos, J.S.; Martínez-Rubio, D.; Millán, J.M.; Rodrigo, R.; Sanz, P.; Seco-Cervera, M.; Sevilla, T.; Tapia, A.; Pallardó, F.V.; Antioxidants 2020, 9, 313.

Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich’s ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies.

The repeat variant in MSH3 is not a genetic modifier for spinocerebellar ataxia type 3 and Friedreich’s ataxia

Wai Yan Yau, Mafalda Raposo, Conceição Bettencourt, Robyn Labrum, João Vasconcelos, Michael H Parkinson, Paola Giunti, Nicholas W Wood, Manuela Lima, Henry Houlden, , Brain, , awaa043, https://doi.org/10.1093/brain/awaa043

MSH3 is a DNA mismatch repair gene whose product is essential for CAG repeat expansion and whose inactivation limits the expansion (Dragileva et al., 2009). The study conducted by Flower et al. demonstrates that a three-repeat allele in the mismatch repair gene MSH3 has potential disease-modifying effect on Huntington’s disease and myotonic dystrophy type 1 (DM1) (Flower et al., 2019), both of which are CAG repeat expansion disorders with distinct phenotypic features. The authors postulated that these effects are mediated through the influence of the MSH3 variant on the rate of somatic expansion.

Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase

Rosa Purroy, Marta Medina-Carbonero, Joaquim Ros, Jordi Tamarit; Redox Biology, Volume 32, 2020, 101520, doi:10.1016/j.redox.2020.101520.


We identified two proteins with altered redox status in frataxin-deficient NRVMs: electron transfer flavoprotein-ubiquinone oxidoreductase and dihydrolipoyl dehydrogenase (DLDH). As DLDH is involved in protein-bound lipoic acid redox cycling, we analyzed the redox state of this cofactor and we observed that lipoic acid from pyruvate dehydrogenase was more oxidized in frataxin-deficient cells. Also, by targeted proteomics, we observed a decreased content on the PDH A1 subunit from pyruvate dehydrogenase. Finally, we analyzed the consequences of supplementing frataxin-deficient NRVMs with the PDH cofactors thiamine and lipoic acid, the PDH activator dichloroacetate and the antioxidants N-acetyl cysteine and Tiron. Both dichloroacetate and Tiron were able to partially prevent lipid droplet accumulation in these cells. Overall, these results indicate that frataxin-deficient NRVMs present an altered thiol-redox state which could contribute to the cardiac pathology.

Calpain-Inhibitors Protect Frataxin-Deficient Dorsal Root Ganglia Neurons from Loss of Mitochondrial Na+/Ca2+ Exchanger, NCLX, and Apoptosis

Elena Britti, Fabien Delaspre, Jordi Tamarit & Joaquim Ros; Res (2020). doi:10.1007/s11064-020-03020-3

Calpains are calcium-dependent proteases activated in apoptotic cell death and neurodegeneration. Friedreich Ataxia is a neurodegenerative rare disease caused by frataxin deficiency, a mitochondrial protein. Dorsal root ganglion (DRG) sensory neurons are among the cellular types most affected in this disease. We have previously demonstrated that frataxin-deficient DRGs show calpain activation, alteration in calcium levels and decreased content of the Na+/Ca2+ exchanger (NCLX). This transporter is involved in mitochondrial calcium efflux. In this study, we have performed a time-course analysis of several parameters altered in a frataxin-deficient DRGs. These include decline of NCLX levels, calcium accumulation, mitochondrial depolarization, α-fodrin fragmentation and apoptotic cell death. Furthermore, we have analysed the effect of the calpain inhibitors MDL28170 and Calpeptin on these parameters. We have observed that these inhibitors increase NCLX levels, protect sensory neurons from neurite degeneration and calcium accumulation, and restore mitochondrial membrane potential. In addition, calpain 1 reduction alleviated neurodegeneration in frataxin-deficient DRG neurons. These results strengthen the hypothesis of a central role for calcium homeostasis and calpains in frataxin-deficient dorsal root ganglia neurons.

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Arabela Sanz, Marta Llovera, Rosa Purroy, Stefka Mincheva-Tasheva, Jordi Tamarit, Joaquim ROS; bioRxiv 2020.04.09.034017; doi: https://doi.org/10.1101/2020.04.09.034017

Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential. Accordingly, apoptotic markers and neurite degeneration are reduced resulting in cell survival recovery with calcitriol supplementation. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Particle-mediated delivery of frataxin plasmid to a human sensory neuronal model of Friedreich's ataxia

Ewa Czuba-Wojnilowicz, Serena Viventi, Sara E. Howden, Simon Maksour, Amy E. Hulme, Christina Cortez-Jugo, Mirella Dottori and Frank Caruso; Biomater. Sci., 2020, Advance Article doi:10.1039/C9BM01757G

Increasing frataxin protein levels through gene therapy is envisaged to improve therapeutic outcomes for patients with Friedreich's ataxia (FRDA). A non-viral strategy that uses submicrometer-sized multilayered particles to deliver frataxin-encoding plasmid DNA affords up to 27 000-fold increase in frataxin gene expression within 2 days in vitro in a stem cell-derived neuronal model of FRDA.

Long-term voluntary running prevents the onset of symptomatic Friedreich’s ataxia in mice

Henan Zhao, Beven M. Lewellen, Rebecca J. Wilson, Di Cui, Joshua C. Drake, Mei Zhang & Zhen Yan; Sci Rep 10, 6095 (2020). doi:10.1038/s41598-020-62952-6

Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.

Progress towards drug discovery for Friedreich’s Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein

Xiulong Shen, Johnathan Wong, Thahza P. Prakash, Frank Rigo, Yanjie Li, Marek Napierala, David R. Corey; Bioorganic & Medicinal Chemistry,
2020, 115472, doi:10.1016/j.bmc.2020.115472.

We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. We now report testing of “gapmer” oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that increases binding affinity. We find that gapmer antisense oligonucleotides are several fold more potent activators of FXN expression relative to previously tested compounds. The potency of FXN activation is similar to a potent benchmark gapmer targeting the nuclear noncoding RNA MALAT-1, suggesting that our approach has potential for developing more effective compounds to regulate FXN expression in vivo.

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq, Laurent Monassier, Helene Puccio; bioRxiv 2020.03.31.015255; doi:10.1101/2020.03.31.015255

AAV-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administrated, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or in off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level, but significant toxicity to the mitochondria and heart above 20-fold. We show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of mitochondria respiratory chain, ultrastructure and homeostasis, which lead to myofilaments alteration, cell death and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriately vector potency, long term safety and biomarkers to monitor such events.