Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions

David R. Lynch, Garrett Farmer; Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions. Neuronal Signal 25 June 2021; 5 (2): NS20200093. doi: doi:10.1042/NS20200093

Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.

The Oxford-Harrington Rare Disease Centre initiates first disease priority area: Friedreich’s Ataxia

27 May 2021, The Oxford-Harrington Rare Disease Centre is redoubling efforts to develop a therapeutics programme for Friedreich’s Ataxia.

OHC will be building on the long history of important contributions to the FA field by Oxford researchers. As a first step in this new journey, with the support of EndFA, a philanthropic partner focused on FA, the OHC has recruited a new Research Facilitator in Friedreich’s Ataxia. Dr Geoffrey Denwood joined the OHC at the University of Oxford site in April 2021, and will dedicate his time and expertise into coordinating the activities of the OHC in FA. Dr Denwood will evaluate the current status of FA translational research and therapeutics development locally and globally, then work to fund and implement an OHC programme harnessing the best expertise and most promising therapeutic opportunities.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

ERDEM M. TERZI, VLADISLAV O. SVIDERSKIY, SAMANTHA W. ALVAREZ, GABRIELLE C. WHITEN, RICHARD POSSEMATO; Science Advances 26 May 2021: Vol. 7, no. 22, eabg4302, DOI: 10.1126/sciadv.abg4302 

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.

Larimar Therapeutics Reports FDA Clinical Hold on CTI-1601 and Termination of Recently Announced Private Placement Financing

BALA CYNWYD, Pa., May 25, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the United States Food and Drug Administration (FDA) has placed a clinical hold on the CTI-1601 clinical program and that the company will not be closing a previously announced private placement financing. 

The clinical hold follows the previous notification by Larimar to the FDA of mortalities which occurred at the highest dose levels in an ongoing 180-day non-human primate (NHP) toxicology study, which is designed to support extended dosing of patients with CTI-1601. 

In the clinical hold letter, the FDA stated it needs a full study report from the ongoing NHP study and Larimar may not initiate additional clinical trials until the company has submitted the report and received notification from the agency that additional clinical trials may commence.

Generation of a Friedreich’s Ataxia patient-derived iPSC line USFi001-A

Mariana Burgos Angulo, Jiajia Yang, Mariana A. Argenziano, Alexander C. Bertalovitz, Maliheh Najari Beidokhti, Thomas V. McDonald; Stem Cell Research, Volume 54, 2021, 102399, doi:10.1016/j.scr.2021.102399. 

We generated an induced pluripotent stem cell (iPSC) line from an FA patient with a homozygous GAA expansion in intron 1 of the FXN gene. The IPSCs display pluripotent cell morphology, expression of pluripotency markers, normal karyotype, and the capability to differentiate into all three germ layers.

Larimar Therapeutics Announces $95 Million Private Placement Financing

BALA CYNWYD, Pa., May 21, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that it has executed a securities purchase agreement to raise gross proceeds of approximately $95 million in a private placement financing of common stock.

Larimar intends to use the net proceeds from the private placement to support the clinical development of CTI-1601, for additional research and development and for working capital and general corporate purposes.

Larimar Therapeutics Receives European Medicines Agency Priority Medicines (PRIME) Designation for CTI-1601 in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 20, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation to CTI-1601 for the treatment of FA. 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 look forward to CTI-1601’s continued clinical development and to the planned initiations of our Jive open label extension and pediatric multiple-ascending dose trials, which are expected in the second half of the year. 

In addition to PRIME designation, CTI-1601 has also been granted Rare Pediatric Disease designation, Fast Track designation and Orphan Drug designation by the U.S. Food and Drug Administration and Orphan Drug Designation by the European Commission.

Reata Announces that The FDA Has Asked The Company to Request a Pre-NDA Meeting for Omaveloxolone for the Treatment of Friedreich’s Ataxia

PLANO, Texas, May 19, 2021 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it received a communication from the Division of Neurology Products 1 (“Division”) of the U.S. Food and Drug Administration (“FDA”) stating that, after a preliminary review of briefing materials for an upcoming Type C meeting, a pre-NDA meeting is the most appropriate format for a discussion of the development program for omaveloxolone in Friedreich’s ataxia (“FA”). The Division suggested that the Company withdraw the current meeting request for a Type C meeting and instead request a pre-NDA meeting, which the Division will grant upon receipt. The Division asked the Company to focus the new briefing package on questions, issues, and needs applicable to a pre-NDA meeting. As requested by the FDA, the Company plans to withdraw the current request for a Type C meeting and submit a request for a pre-NDA meeting as soon as practicable. 

“We welcome the opportunity to have a pre-NDA meeting regarding our omaveloxolone development program for the treatment of patients with FA,” said Warren Huff, Reata’s President and Chief Executive Officer. “We look forward to working with the FDA on our goal of securing the regulatory review and approval necessary to make omaveloxolone available to patients with FA.”

Reverse phase protein array reveals correlation of retinoic acid metabolism with cardiomyopathy in Friedreich’s ataxia

Jill S. Napierala, Kimal Rajapakshe, Amanda Clark, Yu-Yun Chen, Shixia Huang, Clementina Mesaros, Peining Xu, Ian A. Blair, Lauren A. Hauser, Jennifer Farmer, David R. Lynch, Dean P. Edwards, Cristian Coarfa, Marek Napierala; Molecular & Cellular Proteomics, DOI:10.1016/j.mcpro.2021.100094 

 Among sixty-two fibroblast samples (44 FRDA and 18 controls) analyzed, 30 proteins/phosphoproteins were significantly changed in FRDA fibroblasts compared to control cells (p<0.05), mostly representing signaling molecules and metabolic enzymes. As expected, frataxin (FXN) was significantly downregulated in FRDA samples, thus serving as an internal control for assay integrity. Extensive bioinformatic analyses were conducted to correlate differentially expressed proteins with critical disease parameters (e.g. selected symptoms, age of onset, GAA sizes, FXN levels, FARS scores). Members of the integrin family of proteins specifically associated with hearing loss in FRDA. Also, RPPA data, combined with results of transcriptome profiling, uncovered defects in the retinoic acid (RA) metabolism pathway in FRDA samples. Moreover, expression of ALDH1A3 differed significantly between cardiomyopathy positive and negative FRDA cohorts, demonstrating that metabolites such as retinol, retinal or RA could become potential predictive biomarkers of cardiac presentation in FRDA.

Exicure, Inc. Reports First Quarter 2021 Financial Results and Corporate Progress

CHICAGO & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Exicure, Inc.® (NASDAQ: XCUR), a pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA™) technology, today reported financial results for the quarter ended March 31, 2021 and provided an update on corporate progress.

Neurology – XCUR-FXN: The Company hosted a virtual R&D Day in January 2021 to discuss progress within its neurology pipeline, which included an overview of the Company’s XCUR-FXN path to clinical validation for the treatment of Friedreich’s Ataxia (FA). During the first quarter of 2021, the Company continued to advance preclinical and IND-enabling studies of XCUR-FXN in FA and disclosed encouraging preclinical mouse data, demonstrating significant upregulation of XCUR-FXN components in the brain and spinal cord. The Company believes these data support the potential for XCUR-FXN as a disease-modifying treatment for the disease. The Company is on track with prior guidance to submit an IND for XCUR-FXN in FA by year-end 2021 and expects to initiate a first-in-patient Phase 1b clinical trial of XCUR-FXN in FA in the first half of 2022.