Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction

Marku, A.; Galli, A.; Marciani, P.; Dule, N.; Perego, C.; Castagna, M.; Cells 2021, 10, 2841. doi:10.3390/cells10112841 

Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.

FDA refusal of Stealth Bio drug shows challenges of ultra-rare disease studies

https://medcitynews.com

The FDA refused to review Stealth BioTherapeutics’ Barth syndrome drug, telling the company results in a study of just eight patients are insufficient to support its submission. The impasse highlights the challenges of testing drugs for ultra-rare diseases. Barth is so rare that Stealth is unsure it can recruit patients to run a new study. Stealth said it is evaluating its next steps and expects to provide an update in early November. But Barth is not the only disease at stake. Elamipretide was developed as a way to treat mitochondrial problems in a range of disorders. Cardiomyopathy, the heart muscle weakness that develops in Barth, also develops in two other rare disorders, Duchenne muscular dystrophy and Friedreich’s ataxia. When Stealth reported its second quarter financial results in August, executives said they hope to begin testing elamipretide in Duchenne patients with cardiomyopathy in the first half of next year. An open label Phase 2a study is also expected in Friedreich’s ataxia. Stealth is also evaluating its drug in other diseases.

Mitochondrial Iron-Sulfur Cluster Biogenesis and Neurological Disorders

Arthavan Selvanathan, Bindu Parayil Sankaran; Mitochondrion, 2021, doi:10.1016/j.mito.2021.10.004.

This review focuses on the disorders of ISC biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features will be discussed, providing a reference point for clinicians diagnosing and managing these patients. Therapies are mostly supportive at this stage. However, the improved understanding of the pathophysiology of these conditions could pave the way for disease-modifying therapies in the near future.

Variables affecting pricing of orphan drugs: the Italian case

Claudio Jommi, Elisabetta Listorti, Federico Villa, Simone Ghislandi, Armando Genazzani, Agnese Cangini & Francesco Trotta; Orphanet J Rare Dis 16, 439 (2021). doi:10.1186/s13023-021-02022-w

Our results suggest that value arguments and sustainability (dimension of the target population and its impact on budget impact) issues are considered for orphan drugs pricing: the role played by sustainability is systematically supported by our results. A more transparent and reproducible price negotiation process for orphan drugs is needed in Italy.

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia

Schur GM, Dunn J, Nguyen S, Dedio A, Wade K, Tamaroff J, Mitta N, Wilson N, Reddy R, Lynch DR, McCormack SE.; J Neurol. 2021 Oct 15. doi: 10.1007/s00415-021-10821-1. Epub ahead of print. PMID: 34652504. 

In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study

Khan, W., Corben, L.A., Bilal, H., Vivash, L., Delatycki, M.B., Egan, G.F. and Harding, I.H. (2021), Mov Disord. doi:10.1002/mds.28825 

Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness.

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V, Stuart G, Uzun O, McLeod KA, Ilina M, Adwani S, Daubeney P, Delle Donne G, Linter K, Jones CB, Bharucha T, Cervi E, Kaski JP.; Arch Dis Child. 2021 Oct 5:archdischild-2021-322455. doi: 10.1136/archdischild-2021-322455. Epub ahead of print. PMID: 34610949. 

This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

Highlighting the Significant Strides Made in Friedreich Ataxia Care

NeurologyLive. October 1, 2021. David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, discussed why omaveloxolone’s recent success speaks to the progress made within the FA treatment space.

Reata Pharmaceuticals Plans NDA Submission for Omaveloxolone in First Quarter of 2022 Following Completion of Pre-NDA Meeting with FDA

September 30, 2021. PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it has completed its pre-New Drug Application (“NDA”) meeting with the United States Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia and reaffirmed its plan to submit an NDA in the first quarter of 2022.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Li Li, Devon M. Conradson, Vinita Bharat, Min Joo Kim, Chung-Han Hsieh, Paras S. Minhas, Amanda M. Papakyrikos, Aarooran Sivakumaran Durairaj, Anthony Ludlam, Katrin I. Andreasson, Linda Partridge, Michael A. Cianfrocco & Xinnan Wang; Nature Metabolism. 2021 Sep;3(9):1242-1258. DOI: 10.1038/s42255-021-00443-2. PMID: 34504353. 

 Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.