Targeting 3′ and 5′ untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression

Yanjie Li, Jixue Li, Jun Wang, David R Lynch, Xiulong Shen, David R. Corey, Darshan Parekh, Balkrishen Bhat, Caroline Woo, Jonathan J Cherry, Jill S Napierala, Marek Napierala, Nucleic Acids Research, 2021;, gkab954, doi:10.1093/nar/gkab954 

Friedreich’s ataxia (FRDA) is a severe multisystem disease caused by transcriptional repression induced by expanded GAA repeats located in intron 1 of the Frataxin (FXN) gene encoding frataxin. FRDA results from decreased levels of frataxin; thus, stabilization of the FXN mRNA already present in patient cells represents an attractive and unexplored therapeutic avenue. In this work, we pursued a novel approach based on oligonucleotide-mediated targeting of FXN mRNA ends to extend its half-life and availability as a template for translation. We demonstrated that oligonucleotides designed to bind to FXN 5′ or 3′ noncoding regions can increase FXN mRNA and protein levels. Simultaneous delivery of oligonucleotides targeting both ends increases efficacy of the treatment. The approach was confirmed in several FRDA fibroblast and induced pluripotent stem cell-derived neuronal progenitor lines. RNA sequencing and single-cell expression analyses confirmed oligonucleotide-mediated FXN mRNA upregulation. Mechanistically, a significant elongation of the FXN mRNA half-life without any changes in chromatin status at the FXN gene was observed upon treatment with end-targeting oligonucleotides, indicating that transcript stabilization is responsible for frataxin upregulation. These results identify a novel approach toward upregulation of steady-state mRNA levels via oligonucleotide-mediated end targeting that may be of significance to any condition resulting from transcription downregulation.

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.