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.