European Reference networks for rare diseases: what is the conceptual framework?

Véronique Héon-Klin, Orphanet Journal of Rare Diseases 201712:137 doi:10.1186/s13023-017-0676-3

In February 2017, 24 European Reference Networks (ERNs) were established in a European legal framework, of which 23 are dedicated to rare or low prevalence complex diseases or conditions. More than 300 hospitals and 900 highly specialised teams are participating in the approved ERN.

The ERNs are an opportunity to explore these changes and turn them into assets for patients with unmet needs. If we succeed in promote knowledge exchange in such a way that patients will only be treated in duly justified cases in the “other” MS, then “the European social model in health” can be preserved under the current European treaties.

Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease

Yabe I, Sasaki H.; Brain Nerve. 2017 Aug;69(8):913-924. doi: 10.11477/mf.1416200842.
[Article in Japanese]
We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.

Cerebral Abnormalities in Friedreich Ataxia: A Review

Louisa P. Selvadurai, Ian H. Harding, Louise A. Corben, Nellie Georgiou-Karistianis, Neuroscience & Biobehavioral Reviews, Available online 18 August 2017, ISSN 0149-7634, doi:10.1016/j.neubiorev.2017.08.006.

However, cerebral abnormalities in FRDA are being increasingly documented via multiple neuroimaging techniques. Understanding the nature and implications of cerebral abnormalities in FRDA provides more comprehensive knowledge of nervous system involvement in this disorder and increases the prospects of identifying effective treatment targets. We review the cerebellar and the cerebral involvement with a focus on the emerging in vivo human neuroimaging findings suggesting wide-spread cerebral involvement, including aberrant cerebellar-cerebral connectivity. We synthesise the findings by proposing potential mechanisms that may drive these effects. Finally, we identify future research directions which, we argue, will lead to a better understanding of the extent and potential mechanisms of cerebral aberrations in FRDA.

Tocotrienols: the unsaturated sidekick shifting new paradigms in vitamin E therapeutics

Madhu M. Kanchi, Muthu K. Shanmugam, Grishma Rane, Gautam Sethi, Alan P. Kumar, Drug Discovery Today, 2017, ISSN 1359-6446, doi:10.1016/j.drudis.2017.08.001.

Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials. This review provides a comprehensive update on the little-known therapeutic potentials of tocotrienols, which tocopherols lack in a variety of inflammation-driven diseases.

Remarks: EPI-743, sin: alpha-tocotrienol quinone, vatiquinone or Vincerinone. BioElectron Technology Corporation (Edison Pharmaceutical)

Targeting Mitochondrial Dysfunction in Neurodegenerative Disease

The Dana Foundation. By Kayt Sukel, August 15, 2017

It’s long been known that the brain is an energy glutton: Most estimates suggest that it requires about 20 percent of the body’s total energy stores to work effectively. That energy is produced by mitochondria, specialized rod-shaped organelles in every cell in the body. So perhaps it is no surprise that problems with mitochondrial function in neurons have been linked to a host of progressive neurodegenerative disorders—one of which is Friedreich’s ataxia, a rare but devastating disease that progressively kills off nerve cells in the brain and spinal cord. Now, scientists at the University of California, Davis have identified how frataxin, the gene that causes Friedreich’s ataxia, affects mitochondrial function. That understanding may lead to new, more effective potential treatments for Friedreich’s ataxia as well as other forms of neurodegenerative disease.

Cortopassi hopes to take dimethyl fumarate (DMF) to clinical trial for Friedreich’s ataxia patients soon. He also thinks measuring mitochondrial number could be an important biomarker to test the efficacy of treatments for other neurodegenerative disorders as well. Manfredi agrees.

Mechanisms of unexpected death and autopsy findings in Friedreich ataxia

Roger W Byard, , John D Gilbert; Medicine, Science and the Law, First published date: August-13-2017, Doi:10.1177/0025802417723809

A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. Sudden death due to cardiac disease, resulting in presentation for medicolegal autopsy, may be the presenting feature at all ages, including childhood.
The reported case demonstrates sudden death due to cardiac disease in a woman with an established diagnosis of Friedreich ataxia. Death may, however,be due to a wide range of other vascular, pulmonaryor endocrine diseases, which should be checked for at autopsy. Very rarely, sudden cardiac death may be the presenting feature of this condition.

FDA Confirms That Use of mFARS as Primary Endpoint in Part 2 of the MOXIe Trial Can Support Approval of Omaveloxolone in Friedreich’s Ataxia

RVING, Texas, Aug. 14, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or the “Company”), a clinical-stage biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) confirmed that the modified Friedreich’s Ataxia Rating Scale (mFARS) is an acceptable primary endpoint for Part 2 of the MOXIe trial for omaveloxolone in Friedreich’s ataxia (FA).

Part 2 of the MOXIe trial will be a double-blind, randomized, placebo-controlled, multi-center, international trial designed to evaluate the safety, tolerability, and efficacy of omaveloxolone in patients with FA. The trial will enroll approximately 100 FA patients randomized evenly to either 150 mg of omaveloxolone or placebo. The primary endpoint of the trial will be the change from baseline in mFARS of omaveloxolone compared to placebo at 48 weeks. Additional endpoints will include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and Clinical Global Impression of Change. The Company has initiated screening patients for Part 2 of MOXIe and plans to randomize the first patient during the second half of 2017.

Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner

J. Augustyniak, J. Lenart, M. Zychowicz, P. P. Stepien, L. Buzanska. Biogerontology (2017) 18: 665. doi:10.1007/s10522-017-9718-4

Idebenone, the synthetic analog of coenzyme Q10 can improve electron transport in mitochondria. Therefore, it is used in the treatment of Alzheimer’s disease and other cognitive impairments. However, the mechanism of its action on neurodevelopment is still to be elucidated. Here we demonstrate that the cellular response of human induced pluripotent stem cells (hiPSC) to idebenone depends on the stage of neural differentiation. When: neural stem cells (NSC), early neural progenitors (eNP) and advanced neural progenitors (NP) have been studied a significant stimulation of mitochondrial biogenesis was observed only at the eNP stage of development. This coexists with the enhancement of cell viability and increase in total cell number. In addition, we report novel idebenone properties in a possible regulation of neural stem cells fate decision: only eNP stage responded with up-regulation of both neuronal (MAP2), astrocytic (GFAP) markers, while at NSC and NP stages significant down-regulation of MAP2 expression was observed, promoting astrocyte differentiation. Thus, idebenone targets specific stages of hiPSC differentiation and may influence the neural stem cell fate decision.

Furthermore, the specific for eNP upregulation of all tested genes involved in the mitochondrial biogenesis as well as significant upregulation of viability may suggest that eNP stage is the “developmental window of sensitivity” for the neuroprotective function of the idebenone. More research is needed to elucidate the effect of idebenone on mitochondrial biogenesis and stem cell fate decision during neural differentiation, however, based on the presented results we can strongly support the hypothesis that idebenone protective effect is developmental stage dependent and that future targeted treatment of the selected stage of neural development may exert better therapeutic effect.

Reversible axonal dystrophy by calcium modulation in frataxin-deficient sensory neurons of YG8R mice

Belén Mollá, Diana C. Muñoz-Lasso, Fatima Riveiro1, Arantxa Bolinches-Amorós, Federico V. Pallardó, Angel Fernandez-Vilata, Maria D. Vaya, Francesc Palau and Pilar Gonzalez-Cabo; Front. Mol. Neurosci. doi:10.3389/fnmol.2017.00264

We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhD Michele Yang, MD Peter Bauer, MD Arnulf H. Koeppen, MD; Journal of Neuropathology & Experimental Neurology, Volume 76, Issue 8, 1 August 2017, Pages 665–675, doi:10.1093/jnen/nlx047

The pathologic phenotype in homozygous and compound heterozygous FA is determined by residual frataxin levels rather than unique mutations.