Effects of tocotrienol supplementation in Friedreich’s ataxia: A model of oxidative stress pathology

Alessandra Bolotta, Antonella Pini, Provvidenza M Abruzzo, Alessandro Ghezzo, Alessandra Modesti, Tania Gamberi, Carla Ferreri, Francesca Bugamelli, Filippo Fortuna, Silvia Vertuani, Stefano Manfredini, Cinzia Zucchini, Marina Marini; Experimental Biology and Medicine. Dec. 2019, doi:10.1177/1535370219890873.

Oxidative stress is involved in the pathogenesis of Friedreich's ataxia (FRDA), a genetic disorder causing neurodegeneration due to the dramatic reduction in the expression of frataxin. To date, no cure is available for FRDA patients. In some countries, FRDA patients assume idebenone in order to counteract the effects of frataxin deficiency. We demonstrate that idebenone treatment alone is not able to abrogate oxidative stress in FRDA patients, whereas the combined treatment with tocotrienols might be more efficient and perhaps produce clinical improvement. In fact, a decrease in oxidative stress and inflammation markers can be seen after two months and is more pronounced after one year of treatment. This is, in our opinion, valuable information for clinicians, since idebenone is the treatment of choice for FRDA patients in some countries.

The Friedreich’s Ataxia Research Alliance Promotes Jennifer Farmer, MS to Chief Executive Officer

PRESS RELEASE GlobeNewswire, Dec. 5, 2019

DOWNINGTOWN, Pa., Dec. 05, 2019 (GLOBE NEWSWIRE) -- The Board of Directors at The Friedreich’s Ataxia Research Alliance (FARA) today announced the promotion of Jennifer Farmer, MS to the role of Chief Executive Officer (CEO).

L’Associació Francesa de l’atàxia de Friedreich concedeix una ajuda de 25.000 € per validar el potencial terapèutic del calcitriol per tractar aquesta malaltia rara

IRB-Lleida, Dijous, 5 de desembre de 2019
L'Associació Francesa de l'Atàxia de Friedreich ha concedit una ajuda de 25.000 € al Grup de Recerca Bioquímica de l'Estrès Oxidatiu de l'Institut de Recerca Biomèdica de Lleida (IRBLleida) per validar el potencial terapèutic del calcitriol, la forma activa de la vitamina D, per tractar aquesta malaltia. L'investigador principal d'aquest projecte és el doctor Fabien Delaspre.

Les recerques actuals, que s'acabaran de confirmar amb aquest estudi, han demostrat que es tracta d'un model satisfactori per estudiar l'atàxia de Friedreich, ja que mostren nivells baixos (però no nuls) de frataxina i signes de disfunció locomotora.

Friedreich’s Ataxia: Case series and the Additive Value of Cardiovascular Magnetic Resonance

Mavrogeni Sophie, Giannakopoulou Aikaterini, Katsalouli Marinab, Pons Roser Maria, Papavasiliou Antigoni, Kolovou Genovefa, Noutsias Michel, Papadopoulos George, Karanasios Evangelos, Chrousos George P.; Journal of Neuromuscular Diseases, vol. Pre-press, no. Pre-press, pp. 1-7, 2019 DOI: 10.3233/JND-180373

The combination of classical diagnostic indices and CMR may reveal early asymptomatic FA-CM and motivate the early initiation of cardiac treatment. Furthermore, these indices can be also used to validate specific treatment targets in FA, potentially useful in the prevention of FA-CM.

A rare disease patient/caregiver perspective on fair pricing and access to gene-based therapies

White, W.; Gene Ther (2019) doi:10.1038/s41434-019-0110-7

Gene-based therapies are changing the landscape of medicine for patients with rare diseases. Companies should not automatically assume that the combination of the “gene therapy” label and a small patient population justifies high prices. Value determination methods need to provide fair incentives and outcomes to industry, payers, regulators, and especially patients—the courageous pioneers who need equitable and sustainable access to life-changing gene-based therapies.

Pediatric Neuromuscular Disorders

Christopher Michel, Christopher Collins, Pediatric Clinics of North America, 67(1), 45–57. doi:10.1016/j.pcl.2019.09.002

Neuromuscular disorders are pathologies that can severely affect the quality of life as well as longevity of patients. The most common disorders include cerebral palsy and myelodysplasia. The orthopedic manifestations of these disorders can be treated operatively or nonoperatively. Both focus on the prolongation of mobility and preservation of ambulatory capacity for patients.

KEYWORDS:
Cerebral palsy; Duchenne muscular dystrophy; Friedreich ataxia; Marfan syndrome; Meningocele; Myelomeningocele; Pediatric neuromuscular disorders; Spinal muscular atrophy

A network-based approach to uncover microRNA-mediated disease comorbidities and potential pathobiological implications

Shuting Jin, Xiangxiang Zeng, Jiansong Fang, Jiawei Lin, Stephen Y. Chan, Serpil C. Erzurum & Feixiong Cheng; npj Syst Biol Appl 5, 41 (2019) doi:10.1038/s41540-019-0115-2

Beyond genetic analysis, shared patterns of gene expression have raised possibilities to inspect disease–disease relationships.6 Alteration and dysregulation of gene expressions are caused by several biological mechanisms, including microRNA (miRNA) dysregulation.

International perspectives on the implementation of reproductive carrier screening

Martin B. Delatycki Fowzan Alkuraya Alison Archibald Carlo Castellani Martina Cornel Wayne W. Grody Lidewij Henneman Adonis Ioannides Edwin Kirk Nigel Laing Anneke Lucassen John Massie Juliette Schuurmans Meow‐Keong Thong Irene van Langen Joël Zlotogora (2019). Prenatal Diagnosis. doi:10.1002/pd.5611

The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X‐linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions.
A national screening programme for the prevention of Friedreich ataxia has been running since 2011. It is offered to individuals of child bearing age who originate from the Paphos district of Cyprus and is based on the high frequency of carriers in this section of the population which is estimated to be about 1 in 11. Referrals are made by primary care doctors or obstetricians and testing is for the common GAA repeat expansion in intron 1 of the FXN gene.

Possible Mechanisms of Biological Effects Observed in Living Systems during 2H/1H Isotope Fractionation and Deuterium Interactions with Other Biogenic Isotopes

Basov, A.; Fedulova, L.; Vasilevskaya, E.; Dzhimak, S. ; Molecules 2019, 24, 4101. doi:10.3390/molecules24224101

Data on the efficacy and metabolic pathways of the therapy also considered 2H-modified drinking and diet for some diseases, such as Alzheimer’s disease, Friedreich’s ataxia, mitochondrial disorders, diabetes, cerebral hypoxia, Parkinson’s disease, and brain cancer.
The effect of isotope exchange on catalytic complexes in some organelles (mitochondria, peroxisome, and lysosome) can change the intensity of metabolic processes at the cellular level as well as substantially modify the resistance or response of biological tissue.
Friedreich’s ataxia was treated by deuterated linoleic and α-linolenic acids, which resulted in rescue of oxidative-stress-challenged cells by decreasing lipid peroxidation, and also deuterated ethyl linoleate (RT001), which recovered mitochondrial function.

The ying and yang of idebenone: Not too little, not too much – cell death in NQO1 deficient cells and the mouse retina

C. Varricchio, K. Beirne, C. Heard, B. Newland, M. Rozanowska, A. Brancale, M. Votruba, Free Radical Biology and Medicine, 2019, doi:10.1016/j.freeradbiomed.2019.11.030.

Beneficial effects of idebenone are dependent on the expression of NQO1 in cells. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials.