Iron Homeostasis in Health and Disease

Raffaella Gozzelino, and Paolo Arosio; Review: Int. J. Mol. Sci. 2016, 17(1), 130; doi:10.3390/ijms17010130

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 It is established the involvement of this metal in Friedrich’s ataxia, a disease characterized by progressive degeneration of sensory neurons in the dorsal root ganglia caused by a mutation in the frataxin gene. Frataxin plays an essential role in delivering Fe to mitochondrial pathways involved in ISC biogenesis and when its functionality is reduced below a critical threshold, Fe accumulates in mitochondria. Reduced mitochondrial functioning and impaired electron transport chain results in Fe-mediated ROS, which was shown to positively correlate with the severity of Friedrich’s ataxia.

Genome Editing of Structural Variations: Modeling and Gene Correction

Chul-Yong Park, Jin Jea Sung, Dong-Wook Kim, Trends in Biotechnology, Available online 23 March 2016, ISSN 0167-7799, doi:10.1016/j.tibtech.2016.02.011.

Although in vivo gene correction using genetic scissor technology (Meganucleases, ZFNs, TALENs and CRISPR/Cas9) may be available and desirable in the future, effective and cell-specific delivery systems should be developed. These technologies promise to expand our understanding of the mechanism of SVs and our ability to treat SV-related diseases.

For Friedreich's ataxia (FRDA), regions containing GAA repeats from frataxin(FXN) intron 1 were removed by expressing ZFNs targeting 334bp and 896bp upstream of GAA repeats in FRDA fibroblasts and lymphoblasts. The FRDA phenotype was reversed, with increased frataxin expression, when corrected FRDA fibroblasts were converted to iPSCs and differentiated into neurons (Li, Y. et al. (2015)).

Translatability: What does it mean in drug discovery?

Matthew Tudor, Jeffery Hermes, Jing Li (Screening & Protein Science, Merck Research Laboratories,USA), Drug Discovery Today, Available online 26 March 2016, ISSN 1359-6446, doi:10.1016/j.drudis.2016.03.010.

We can develop multiple disease-relevant in vitro and in vivo models as a means of further validation of the initial target hypothesis, and pursue decisive experiments that will enable early no-go calls to be made on targets. However, such surrogate assays can reach the wrong conclusion because they will have imperfect predictivity of the results of a well-designed Phase II clinical trial. Disease relevant assays can serve as ‘gate-keepers’ to inform the probability of the translatability but always have to be interpreted as suggestive rather than definitive.

Friedreich’s ataxia (FA), an autosomal-recessive disease, is caused by a trinucleotide GAA repeat expansion which leads to the reduction of FXN protein expression. The protein function is not entirely understood. Attempts to correct putative FXN mutation sequelae by reversing mitochondrial dysfunction, such as by using ion chelators and antioxidants, are broadly reported. Such symptomatic intervention can be viewed as spreading of bets in addition to direct FXN protein intervention, but the odds are clearly against such nonspecific approaches because of the unknown FXN biology. The more certain bet is on what human genetics is telling us: that restoration of FXN protein levels would be effective. To that end, efforts to improve the rate of transcriptional read-through or splicing would be expected to have higher chances of significantly impacting the clinical state.

Mitochondrial iron overload: causes and consequences

Tracey A Rouault, Current Opinion in Genetics & Development, Volume 38, June 2016, Pages 31-37, ISSN 0959-437X, http://dx.doi.org/10.1016/j.gde.2016.02.004.

The mystery of mitochondrial iron overload diseases — how is mitochondrial iron homeostasis regulated? Despite the fact that much is now known about how mitochondrial Fe-S clusters are assembled and transferred, several major mysteries remain about how mitochondria regulate iron homeostasis in the mitochondrial matrix.The challenge ahead is to identify the full roster of transporters involved in mitochondrial iron homeostasis and to try to identify a regulatory ‘overlord’ that regulates a nuclear transcriptional response to perceived iron deficiency.

Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy

Duncan E. Crombie, Martin F. Pera, Martin B. Delatycki, Alice Pébay, International Journal of Cardiology, Available online 21 March 2016, ISSN 0167-5273, doi:10.1016/j.ijcard.2016.03.040.

Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease mode.

Gastrocnemius and soleus spasticity and muscle length in Friedreich’s ataxia

Sarah C. Milne, Louise A. Corben, Eppie Yiu, Martin B. Delatycki, Nellie Georgiou-Karistianis, Journal of Clinical Neuroscience, Available online 25 March 2016, ISSN 0967-5868, doi:10.1016/j.jocn.2016.01.011.

Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.

Letter: Tissue atrophy and elevated iron concentration in the extrapyramidal motor system in Friedreich ataxia: the IMAGE-FRDA study

Ian H Harding, Parnesh Raniga, Martin B Delatycki, Monique R Stagnitti, Louise A Corben, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F Egan. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2015-312665 Published Online First: 24 March 2016

In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.1–3 The dentate nuclei are iron-laden structures pivotal to movement coordination. However, basal ganglia and midbrain structures also have high iron content, express high levels of frataxin, and play key roles in motor regulation. Furthermore, the dentate nuclei directly innervate the thalamus and red nuclei, and indirectly project to the striatum. This biology motivates the hypothesis that iron-related pathology and/or degeneration within these extrapyramidal stations may also feature in FRDA.

Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases-Friedreich's Ataxia Example.

Li Yanjie, Polak Urszula, Clark Amanda D., Bhalla Angela D., Chen Yu-Yun, Li Jixue, Farmer Jennifer, Seyer Lauren, Lynch David, Butler Jill S., and Napierala Marek. Biopreservation and Biobanking. March 2016, ahead of print. doi:10.1089/bio.2015.0117.

We report the establishment and characterization of an FRDA fibroblast repository, which currently includes 50 primary cell lines derived from FRDA patients and seven lines from mutation carriers.

Vivre avec la maladie de Friedreich : le vécu dysarthrique

Stéphanie Borel, Geneviève Touretz-Hermer, Sandrine Goutaland-Perrin, Peggy Gatignol. Revue Neurologique, Volume 172, Supplement 1, April 2016, Page A163, ISSN 0035-3787, doi:10.1016/j.neurol.2016.01.387.

Cette étude porte sur l’auto-évaluation du handicap de la voix et de la parole des personnes atteintes de la maladie de Friedreich (FRDA). L’utilisation du VHI et du SHI est appropriée pour mettre en évidence les différents profils dysarthriques des participants FRDA. L’utilisation conjointe de ces deux questionnaires semble inadaptée pour des raisons de durée de passation et de non-spécificité par rapport à la maladie de Friedreich. D’autres études sont nécessaires pour mieux connaître l’impact de la FRDA sur la qualité de vie des personnes atteintes, mais aussi l’outil le plus adapté pour le mesurer.

A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia

Michael Bonello and Partha Ray. Case Rep Neurol Med. 2016; 2016: 8342653. Published online 2016 Feb 16. doi:10.1155/2016/8342653

We advocate that vitamin E levels should form part of the initial screen for a patient with young onset progressive ataxia. In the literature there are a number of cases of patients who have been clinically diagnosed prior to genetic testing being widely available. We do recommend that such patients have their frataxin gene checked and if negative have a vitamin E blood level tested as adequate treatment with high dose vitamin E can halt progression of the condition and can be invaluable in genetic counselling.

AVC chez un patient de 25 ans atteint d’une maladie de Friedreich

Cyrielle Coignion, Cyril Goizet, Xavier Vandamme, Revue Neurologique, Volume 172, Supplement 1, April 2016, Page A124, ISSN 0035-3787, doi:10.1016/j.neurol.2016.01.293.

L’atteinte cardiaque serait responsable de 59 % des décès chez ces patients. L’idébénone pourrait avoir un effet protecteur en améliorant la fonction cardiaque. L’association maladie de Friedreich et accidents vasculaires cérébraux est possible par le biais d’une cardiomyopathie hypertrophique et d’une FA qu’il est nécessaire de dépister afin de mettre en place un traitement cardioprotecteur.

Both idebenone and idebenol are localized near the lipid-water interface of the membrane and increase its fluidity

Victoria Gómez-Murcia, Alejandro Torrecillas, Ana M. de Godos, Senena Corbalán-García, Juan C. Gómez-Fernández, Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1858, Issue 6, June 2016, Pages 1071-1081, ISSN 0005-2736, doi:10.1016/j.bbamem.2016.02.034.

"Idebenone is an interesting drug but care should be taken in calling it a coenzyme Q analogue."

Idebenone is sometimes assumed to be an analog of ubiquinone, although their way of interaction with the components of the electron transport chain in mitochondria differs. Whereas ubiquinone-10 carries electrons from complex I and complex II to complex III, idebenone receives electrons from complex I. idebenone shares with ubiquinone the same quinone group, it might also be expected to act as a potent antioxidant, although other studies do not exclude the idea that idebenone may detoxify ROS in a different way to ubiquinone. Since idebenone and idebenol have similar locations, this may explain why this pair does not play exactly the same role as the couple ubiquinone-10/ubiquinol-10 in the mitochondria.

Patent application title: MITOCHONDRIAL PROTEINS CONSTRUCTS AND USES THEREOF

Publication date: 2016-03-17 Patent application number: 20160075745

The method according to claim 19, wherein said functional protein is frataxin, respectively OTC, and said mitochondrial disorder is Friedreich's ataxia or any other disorder associated with deficiency of frataxin or with defective frataxin or, respectively, a disorder associated with a deficiency of OTC or with defective OTC.

New Clinical Trial: Rosuvastatin (Crestor) in Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT02705547 First received: March 5, 2016

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States, 19103
Principal Investigator: David Lynch, MD PhD

This is an open-label study of Rosuvastatin (Crestor) in patients with FRDA. Study subjects will receive 10 mg of Rosuvastatin daily for 3 months.Daily administration of oral tablets of Rosuvastatin, 10 mg.

Context: Friedreich ataxia (FRDA) is a progressive neurodegenerative disease of children and adults for which there is presently no therapy. It has previously been reported that patients with FRDA have lower than expected HDL levels, and recent work by Dr. Blair at the University of Pennsylvania has found that serum ApoA-1 levels in FRDA patients are lower than those in controls. ApoA-1 levels are controlled by HMG-CoA activity, which is elevated in FRDA, and we hope to examine whether HMG-CoA levels can be inhibited by giving statins to patients with FRDA. Inhibition of this pathway has been proposed as a treatment for a variety of neurodegenerative disorders, and we will examine if FRDA may be one of them by looking at various biomarkers in the disease.

Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34

Shen Y, McMackin MZ, Shan Y, Raetz A, David S, Cortopassi G. PLoS ONE 11(3): e0151026. doi:10.1371/journal.pone.0151026

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We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1

Near-infrared spectroscopy for medical applications: Current status and future perspectives

Akikazu Sakudo, Clinica Chimica Acta, Available online 12 February 2016, ISSN 0009-8981, doi:10.1016/j.cca.2016.02.009.

Chronic obstructive pulmonary disease (COPD), cytochrome c oxidase deficiency, metabolic myopathy, Friedreich's ataxia, mitochondrial myopathy as well as neuromuscular diseases and peripheral artery diseases (PAD) and spinal cord injury can be assessed by NIR spectroscopy to detect abnormal oxygen consumption and vasodilation.

An Overview of Direct Somatic Reprogramming: The Ins and Outs of iPSCs (Review )

Siddharth Menon, Siny Shailendra, Andrea Renda, Michael Longaker and Natalina Quarto; Int. J. Mol. Sci. 2016, 17(1), 141; doi:10.3390/ijms17010141 (OPEN ACCESS)

Current techniques produce disease phenotypes, however, the extent of recapitulating all aspects of the disease is still limited. Overall, the vast potential of iPSCs in cell-based therapeutics, drug discovery and disease modeling is clear, though significantly hindered by the lack of understanding of the long-term risks. Until more is understood about the mechanisms of induced pluripotency and differentiation, and the development of extensive screening procedures for genetic aberrations resulting in stable genomes, the use of iPSCs technology remains inadequate for most translational medicine and clinical applications.

The medical experience of a patient with a rare disease and her family

Roberta Garau. Orphanet Journal of Rare Diseases201611:19. DOI: 10.1186/s13023-016-0401-7

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This letter considers the main challenges that people with rare diseases and their families face: delay in diagnosis, lack of appropriate support and information, and impaired access to treatment.