Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

Sina Straub Stephanie Mangesius Julian Emmerich Elisabetta Indelicato Wolfgang Nachbauer Katja S. Degenhardt Mark E. Ladd Sylvia Boesch Elke R. Gizewski; J Neurosci Res. 2020; 00: 1– 13. doi:10.1002/jnr.24701


VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI‐based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments. Positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

Antioxidant Defense Mechanisms and its Dysfunctional Regulation in the Mitochondrial Disease, Friedreich’s Ataxia

S. Chiang, M.L.H. Huang, K.C. Park, D.R. Richardson, Free Radical Biology and Medicine, 2020, doi.org/10.1016/j.freeradbiomed.2020.07.019.

 Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.

Larimar Therapeutics Announces Positive Opinion on Orphan Drug Designation Received from the European Medicines Agency for CTI-1601 for the Treatment of Friedreich’s Ataxia

BALA CYNWYD, Pa., July 28, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Nasdaq:LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) issued a positive opinion on the company’s application for orphan drug designation for CTI-1601, a potential treatment for Friedreich’s ataxia (FA), a rare, progressive, multi-symptom genetic disease that affects the functioning of multiple organs and systems. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein. The U.S. Food and Drug Administration (FDA) previously granted Orphan Drug, Fast Track and Rare Pediatric Disease designations to CTI-1601 for the treatment of FA. Larimar expects that the European Commission, based on this positive opinion of the COMP, will formally grant the orphan drug designation for the European Union (EU) this year.

Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion?

R. Rodríguez, L.; Lapeña, T.; Calap-Quintana, P.; Moltó, M.D.; Gonzalez-Cabo, P.; Navarro Langa, J.A.; Antioxidants 2020, 9, 664. doi:10.3390/antiox9080664

Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those “antioxidant” drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.

Relationship between activity and stability: Design and characterization of stable variants of human frataxin

Ignacio Hugo Castro, Mauro Bringas, Davide Doni, Martin Ezequiel Noguera, Luciana Capece, Martín Aran, Matías Blaustein, Paola Costantini, Javier Santos; Archives of Biochemistry and Biophysics, 2020, 108491, doi:10.1016/j.abb.2020.108491.


In this study, we prepared a set of FXN variants spanning a broad range of conformational stabilities. Variants S160I, S160 M and A204R were more stable than the wild-type and showed similar biological activity. We concluded that the contribution of particular side chains to the conformational stability of FXN might be highly subordinated to their impact on both the protein function and the stability of the functional supercomplex.

Cardiolipin-deficient Cells Have Decreased Levels of the Iron-Sulfur Biogenesis Protein Frataxin

Yiran Li, Wenjia Lou, Alexander Grevel, Lena Böttinger, Zhuqing Liang, JiajiaJi Ji, Vinay A. Patil, Jenney Liu, Cunqi Ye, Maik Hüttemann, Thomas Becker and Miriam L. Greenberg; [published online ahead of print, 2020 Jul 6]. J Biol Chem. 2020;jbc.RA120.013960. doi:10.1074/jbc.RA120.013960

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin-deficiency on iron homeostasis in the mouse myoblast model of BTHS, TAZ-KO (tafazzin knockout) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster (Fe-S) enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective Fe-S biogenesis. We observed decreased levels of Yfh1/frataxin, an essential component of the Fe-S biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in Fe-S biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.

P55 - Characterization of in vivo disposition of CTI-1601: A mitochondria targeted therapy for friedreich’s ataxia

Eric Gonzalez, Erik Wagner, Nicholas Mess, Amy Wang, Mark Payne, David Bettoun, Elizabeth Ottinger, Bonnie Rup, Xin Xu, Drug Metabolism and Pharmacokinetics, Volume 35, Issue 1, Supplement, 2020, Page S38, doi:10.1016/j.dmpk.2020.04.056.

Larimar Therapeutics Announces Dosing of Patients in Third Cohort of Phase 1 SAD Trial of CTI-1601 for Treatment of Friedreich’s Ataxia

BALA CYNWYD, Pa., July 20, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Nasdaq:LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced that patients have been dosed in the third cohort of a Phase 1 clinical trial to evaluate the safety and tolerability of single ascending doses (SAD) of CTI-1601 for the treatment of Friedreich’s ataxia (FA). The trial was previously delayed due to the impact of the COVID-19 pandemic. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein.

“We’re pleased that our Phase 1 clinical trial has resumed and we can continue to move forward with our lead product candidate, CTI-1601, which has the potential to become the first frataxin replacement therapy for patients with FA,” said Carole Ben-Maimon, MD, President and Chief Executive Officer of Larimar Therapeutics. “Our highest priority remains the health of our employees and patients especially given the COVID-19 pandemic. We have thoughtfully re-engaged with our clinical site to mitigate the safety risks.”

Additional information on the trial can be found on www.clinicaltrials.gov using the identifier NCT04176991.

Safety and Efficacy of (+)-Epicatechin in Subjects with Friedreich's Ataxia: A Phase II, Open-Label, Prospective Study

Qureshi, M. Y., Patterson, M. C., Clark, V., Johnson, J. N., Moutvic, M. A., Driscoll, S. W., Kemppainen, J. L., Huston, J., 3rd, Anderson, J. R., Badley, A. D., Tebben, P. J., Wackel, P., Oglesbee, D., Glockner, J., Schreiner, G., Dugar, S., Touchette, J. C., & Gavrilova, R. H. (2020). Journal of inherited metabolic disease, 10.1002/jimd.12285. Advance online publication. doi:10.1002/jimd.12285


(+)-EPI was well tolerated over 24 weeks at up to 150 mg/day. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes.

Stress-induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

Ms. Christiana Salami, Ms. Katie Jackson, Ms. Clarisse L. Jose, Mr. Laith Alyass, Mr. Georges-Ibrahim Cisse, Dr. Bishnu P De, Dr. Katie Stiles, Dr. Maria J. Chiuchiolo, Dr. Dolan Sondhi, Dr. Ronald G Crystal, and Dr. Stephen M. Kaminsky. Human Gene Therapy. Ahead of print doi:10.1089/hum.2019.363

The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress.
A one-time intravenous administration of 1011 genome copies of AAVrh.10hFXN, an adeno-associated virus serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls. These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.