AavantiBio lands manufacturing partner in Friedreich's Ataxia program; NC Research Triangle lands another CDMO

June 3, 2021. ENDPOINTNEWS. AavantiBio and Resilience have announced a collaboration to manufacture a pipeline of therapies, including AavantiBio’s Friedreich’s Ataxia program, the company announced Thursday. 

The new facility will double its existing footprint, and support development, clinical and small-scale commercial manufacturing. The site is just a few miles from its current office, and will meet all FDA, EMA and GMP requirements, the company said.

FARA FA Pipeline Webinar - Jun 2, 2021

Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Campbell, C.J.; Pall, A.E.; Naik, A.R.; Thompson, L.N.; Stemmler, T.L.; Int. J. Mol. Sci. 2021, 22, 6006. doi:10.3390/ijms22116006

Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia

Hao Wang, Jonathan Norton, Lin Xu, Nicholas DeMartinis, Rohini Sen, Ankit Shah, Jennifer Farmer, David Lynch; Annals of Clinical and Translational Neurology. 2021 May. DOI: 10.1002/acn3.51373.

Luvadaxistat (also known as TAK-831; NBI-1065844) was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

SAFETY AND EFFICACY OF THE STEM CELL TRANSPLANTATION IN FRIEDREICH’S ATAXIA: A REPORT OF THREE CASES

Riza Azeri, Duygu Koyuncu Irmak, Eda Sun, Erdal Karaöz; Int J Physiother. Vol 8(1), 31-35, February (2021) doi:10.15621/ijphy/2021/v8i1/903 

Case Summary: Here, we report three FRDA cases treated with four consecutive allogeneic transplantations of umbilical cord-derived MSCs with 30 days interval, upon per patient regulatory approvals for advanced cellular therapy. Outcome Measures: The cases were followed up after the treatment in means of the therapeutic effect of the cellular treatment by attenuating the neurological findings and gene expression parameters. Conclusions: Closely followed promising safety and efficacy outcomes demonstrated that the MSC treatment for FRDA might positively affect the clinical results caused by the defect in this genetic-based disease.

An unusual combination of large Eustachian valve in a young patient with Friedreich's ataxia cardiomyopathy

Stylianos A. Karvounaris, Georgios S. Papaetis, Petros P. Mavrommatis; Cardiol J 2021;28(3):498-499. DOI: 10.5603/CJ.2021.0051 According to available research this is the first published description of a large Eustachian valve in a patient with FA-CM.

Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders

Odiba AS, Okoro NO, Durojaye OA, Wu Y., Open Life Sciences. 2021 ;16(1):431-441. DOI: 10.1515/biol-2021-0033.

Molecular biology and biotechnology tools remained important elements in gene therapy. Gene editing/modification (replacement, insertion, and deletion) largely characterizes this field of biological sciences. The idea of gene therapy was implemented clinically about three decades ago as an alternative to the limitations of pharmacotherapy. Approximately 3,000 known clinical trials are on record. Some limitations are associated with gene therapy; and hence, the need to improve on the current strategies. This has resulted in sophisticated tools using viral and nonviral vectors. Although most of the gene therapy studies are directed toward cancer worldwide, other areas of notable disease require the gene therapy approach; and these include primary immunodeficiency disorders (PIDs), hemoglobin, hemophilia B, ocular, and neurodegenerative disorders.

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.