Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Laura Guarga, Xavier Badia, Mercè Obach, Manel Fontanet, Alba Prat, Atonio Vallano, Josep Torrent and Caridad Pontes; Orphanet Journal of Rare Diseases 2019 14:157 doi:10.1186/s13023-019-1121-6

Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut.

Frequency and Genetic Profile of Compound Heterozygous Friedreich’s Ataxia Patients—the Brazilian Experience

Thiago Mazzo Peluzzo, Luciana Cardoso Bonadia, Amanda Donatti, Miriam Coelho Molck, Laura Bannach Jardim, Wilson Marques Jr, Iscia Teresinha Lopes-Cendes, Marcondes C. França Jr. Cerebellum (2019). doi:10.1007/s12311-019-01055-z

There were 143 unrelated patients (128 families), five of which had a single expanded allele. We identified point mutations in three out of these five (3/128 = 2.34%). Two patients had the c.157delC variant, whereas one individual had the novel variant c.482+1G>T. These results indicate that FXN point mutations are rare, but exist in Brazilian patients with FRDA. This has obvious implications for diagnostic testing and genetic counseling.

Keeping heart homeostasis in check through the balance of iron metabolism

Driton Vela; Acta Physiol. Accepted Author Manuscript. doi:10.1111/apha.13324

This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassemia (cardiomyocyte cytosolic and mitochondrial iron overload), friedreich ataxia (assymetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases.

Open label Pilot Study of Oral Methylprednisolone for the Treatment of Patients with Friedreich Ataxia

Patel, M. , Schadt, K. , McCormick, A. , Isaacs, C. , Dong, Y. N. and Lynch, D. R. (2019), Muscle & Nerve. Accepted Author Manuscript. doi:10.1002/mus.26610

Results
In comparisons of participants’ baseline and week 26 visits, only the pediatric cohort's 1MW score showed change (p<0 .05="" br="" change="" did="" measure="" not="" outcome="" primary="" significantly.="" t25fw="" the="">
Discussion
Pediatric participants improved in gait distance in the 1MW, but not significantly in other measures in this overall negative study. Methylprednisolone was generally well tolerated, suggesting that it may be useful for ambulatory children with FRDA if benefit is found with further study.

Neuromuscular disorders: a guide for the orthopaedic surgeon

Catriona Heaver, Simon Hill, Tracey Willis; Neuromuscular disorders: a guide for the orthopaedic surgeon, Orthopaedics and Trauma, doi:10.1016/j.mporth.2019.05.008

Patients with neuromuscular conditions are frequently seen in final professional clinical examinations as they have good clinical signs, which often point towards the underlying diagnosis. This paper outlines some of the most common neuromuscular disorders that you are likely to come across in orthopaedic practise.
Keywords: arthrogryposis, Charcot-Marie-Tooth, Friedreich's ataxia, hereditary sensory motor neuropathy, muscular dystrophy, neuromuscular conditions, poliomyelitis, spinal muscular atrophy

MON-LB030 Muscle Mitochondrial Oxidative Phosphorylation Capacity and Whole Body Glucose Metabolism in Friedreich's Ataxia

Sara Nguyen, Neil Wilson, Darko Stefanovski, G. Maria Gur, Anna Dedio, Kristin Wade, David Lynch, Ravinder Reddy, Andrea Kelly, Michael Rickels, Shana McCormack; Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON–LB030, doi:10.1210/js.2019-MON-LB030

Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes.

Evidence for genetically determined degeneration of proprioceptive tracts in Friedreich ataxia

Brice Marty, Gilles Naeije, Mathieu Bourguignon, Vincent Wens, Veikko Jousmäki, David R. Lynch, William Gaetz, Serge Goldman, Riitta Hari, Massimo Pandolfo, Xavier De Tiège; Neurology Jun 2019, 10.1212/WNL.0000000000007750; DOI: 10.1212/WNL.0000000000007750

This study provides electrophysiologic evidence demonstrating that proprioceptive impairment in FRDA is mostly genetically determined and scarcely progressive after symptom onset. It also positions CKC as a reliable, robust, specific marker of proprioceptive impairment in FRDA.

Deuterated Polyunsaturated Fatty Acids Reduce Oxidative Stress and Extend the Lifespan of C. elegans

Beaudoin-Chabot C, Wang L, Smarun AV, Vidović D, Shchepinov MS and Thibault G (2019). Front. Physiol. 10:641. doi: 10.3389/fphys.2019.00641

Chemically reinforced essential fatty acids (FAs) promise to fight numerous age-related diseases including Alzheimer's, Friedreich's ataxia and other neurological conditions. The reinforcement is achieved by substituting the atoms of hydrogen at the bis-allylic methylene of these essential FAs with the isotope deuterium. This substitution leads to a significantly slower oxidation due to the kinetic isotope effect, inhibiting membrane damage. The approach has the advantage of preventing the harmful accumulation of reactive oxygen species (ROS) by inhibiting the propagation of lipid peroxidation while antioxidants potentially neutralize beneficial oxidative species. Here, we developed a model system to mimic the human dietary requirement of omega-3 in Caenorhabditis elegans to study the role of deuterated polyunsaturated fatty acids (D-PUFAs). Deuterated trilinolenin [D-TG(54:9)] was sufficient to prevent the accumulation of lipid peroxides and to reduce the accumulation or ROS. Moreover, D-TG(54:9) significantly extended the lifespan of worms under normal and oxidative stress conditions. These findings demonstrate that D-PUFAs can be used as a food supplement to decelerate the aging process, resulting in extended lifespan.

DNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria

Luis Bermúdez-Guzmán and Alejandro Leal; Translational Neurodegeneration 20198:14 doi:10.1186/s40035-019-0156-x

Diseases such as Friedreich’s ataxia and MIRAS (caused by POLG mutations) present an extended phenotype, maybe derived from the equal vulnerability that these variants confer to the mitochondria in the whole organism. Even though the clinical difference is evident, still more research is needed to understand the molecular basis of this systemic damage compared with the diseases that tend to present a pathological tropism.

Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich At

Hiroya Naruse, Yuji Takahashi, Hiroyuki Ishiura, Takashi Matsukawa, Jun Mitsui, Yaeko Ichikawa, Masashi Hamada, Jun Shimizu, Jun Goto, Tatsushi Toda, Shoji Tsuji, axia, Internal Medicine, Article ID 2953-19, [Advance publication] Released June 07, 2019, Online ISSN 1349-7235, Print ISSN 0918-2918, doi:10.2169/internalmedicine.2953-19,

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Riccardo Turchi, Flavia Tortolici, Giulio Guidobaldi, Federico Iacovelli, Mattia Falconi, Stefano Rufini, Raffaella Faraonio, Viviana Casagrande, Lorenzo De Angelis, Massimo Federici, Simone Carotti, Maria Francesconi, Maria Zingariello, Sergio Morini, Roberta Bernardini, Maurizio Mattei, Daniele Lettieri-Barbato, Katia Aquilano; bioRxiv 664649; doi:10.1101/664649

Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich's ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.

Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates

Reisman SA, Gahir SS, Lee CY, Proksch JW, Sakamoto M, Ward KW (Reata Pharmaceuticals, Inc., Irving, TX 75063, USA); Drug Des Devel Ther. 2019; 13: 1259–1270.Published online 2019 Apr 17. doi: 10.2147/DDDT.S193889

Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.

Is left ventricular longitudinal strain a good prognostic factor in Friedreich ataxia?

C. Heuze, L. Legrand, A. Diallo, M.L. Monin, C. Ewenczyk, R. Isnard, E. Vicaut, A. Durr, F. Pousset, Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 3, 2019, Page e321, doi:10.1016/j.acvdsp.2019.04.036.

GLS is a predictor of morbimortality but is not superior to LVEF in FRDA patients.

Microvascular pathology in Friedreich cardiomyopathy

Arnulf H. Koeppen, Jiang Qian, Alicia M. Travis, Alyssa B. Sossei, Paul J. Feustel and Joseph E. Mazurkiewicz; Histol Histopathol. 2019 Jun 5:18132. doi: 10.14670/HH-18-132. [Epub ahead of print]


Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69.

Minoryx inicia el primer tratamiento de un paciente con Ataxia de Friedreich en el Hospital La Paz

Mataró (Barcelona)-Charleroi (Bélgica), 4 de mayo de 2019. Minoryx Therapeutics, compañía biotecnológica especializada en el desarrollo de nuevos medicamentos para enfermedades huérfanas, anuncia hoy que ha dosificado con el fármaco leriglitazona (MIN-102) al primer paciente en el ensayo clínico FRAMES de Fase II para el tratamiento de la Ataxia de Friedreich (FRDA).

Minoryx Therapeutics enrôle le premier patient de son essai clinique de phase II dans l’ataxie de Friedreich

Mataró, Barcelone, Espagne et Charleroi, Belgique, le 4 juin 2019 - Minoryx Therapeutics, une société spécialisée dans le développement de nouveaux médicaments contre des maladies orphelines, annonce aujourd'hui qu’un premier dosage de patient a été réalisé dans l’essai clinique FRAMES de phase II sur l’ataxie de Friedreich avec son candidat médicament leriglitazone (MIN-102).

Minoryx Therapeutics announces first patient dosed in the FRAMES phase 2 trial in Friedreich’s Ataxia

Minoryx Therapeutics, a company specializing in the development of new drugs for orphan diseases, today announces that the first patient has been dosed with its lead candidate, leriglitazone (MIN-102), in the phase 2 FRAMES clinical trial in Friedreich’s Ataxia.

Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia

Mittal Jasoliya , Francesco Sacca , Sunil Sahdeo, Frederic Chedin, Chiara Pane, Vincenzo Brescia Morra, Alessandro Filla, Mark Pook, Gino Cortopassi. PLoS ONE 14(6): e0217776. doi:10.1371/journal.pone.0217776

Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.

Efficient Electroporation of Neuronal Cells Using Synthetic Oligonucleotides: Identifying Duplex RNA and Antisense Oligonucleotide Activators of Human Frataxin Expression

Xiulong Shen, Sharon Beasley, Jennifer Putnam, Yanjie Li, Thahza Prakash, Frank Rigo, Marek Napierala, and David Corey. RNA rna.071290.119 Published in Advance May 31, 2019, doi:10.1261/rna.071290.119

We have previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived fibroblast cells. We chose to further test these compounds in induced pluripotent stem cell-derived neuronal progenitor cells (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC’s cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using patient-derived fibroblast cells. A duplex RNA and several antisense oligonucleotides with different combinations of 2’-methoxylethyl (2’-MOE), 2’-fluoro (2’-F), and constrained ethyl (cEt) were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. Our data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FRDA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.

p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia

Helma, R.; Bažantová, P.; Petr, M.; Adámik, M.; Renčiuk, D.; Tichý, V.; Pastuchová, A.; Soldánová, Z.; Pečinka, P.; Bowater, R.P.; Fojta, M.; Brázdová, M. . Molecules 2019, 24, 2078. doi: 10.3390/molecules24112078

In summary, we show that non-B DNA structures formed by TNR (TTC, GAA, CTG, CAG) and simple T-repeat are recognized by p53. Moreover, p53 prefers non-B DNA structures formed by the pyrimidine-rich strands of the investigated repetitive sequences and that the intact C-terminus is responsible for high p53 affinity to TNR non-B DNA structures. Further studies are needed to understand the precise function of p53 TNR non-B DNA recognition in relation to the development of Friedreich’s ataxia or other diseases coupled with TNR expansion.