Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Jeffrey R. Liddell, Antioxidants 2017, 6(3), 65; doi:10.3390/antiox6030065

This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.

Jupiter Orphan Therapeutics Receives Orphan Drug Designation for its Trans-Resveratrol Product JOTROL for Treatment of Friedreich's Ataxia

JUPITER, Fla., Aug. 22, 2017 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT"), Jupiter, FL, today announced that it has received notification from the US Food and Drug Administration (FDA) that its Orphan Drug Designation request for trans-Resveratrol has been granted.

"Orphan Drug Designation serves as an important milestone for JOT as it positions our JOTROL™ product as a potential treatment for FA. We are hopeful that JOTROL™ can ultimately provide a meaningful treatment for FA patients around the world based on the earlier Phase II trial, utilizing resveratrol, conducted by our partner Murdoch Children's Research Institute, Melbourne, Australia ("MCRI"). That trial was an open label trial and generated very encouraging results, where 4 out of 5 very important endpoints were met. We, JOT together with MCRI, expect to repeat these results through a larger placebo controlled study utilizing JOTROL™ to avoid the Gastro Intestinal (GI) tolerability issues.

Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells

Daniela Giustarini, Graziano Colombo, Maria Lisa Garavaglia, Emanuela Astori, Nicola Marcello Portinaro, Francesco Reggiani, Salvatore Badalamenti, Anna Maria Aloisi, Annalisa Santucci, Ranieri Rossi, Aldo Milzani, Isabella Dalle-Donne, Free Radical Biology and Medicine, Available online 12 August 2017, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2017.08.008.

Glutathione (GSH) is the major non-protein thiol in humans and other mammals, which is present in millimolar concentrations within cells, but at much lower concentrations in the blood plasma. GSH and GSH-related enzymes act both to prevent oxidative damage and to detoxify electrophiles. Under oxidative stress, two GSH molecules become linked by a disulphide bridge to form glutathione disulphide (GSSG). Therefore, assessment of the GSH/GSSG ratio may provide an estimation of cellular redox metabolism. Current evidence resulting from studies in human blood, solid tissues, and cultured cells suggests that GSH also plays a prominent role in protein redox regulation via S-glutathionylation.

By immunohistochemistry with anti-GSH antibody, PSSG were also detected in Friedreich's ataxia, an autosomal recessive disorder caused by mutations in the gene encoding frataxin. In particular, in the cervical sections of spinal cord derived from autopsies of individuals with Friedreich's ataxia, immunostaining with anti-GSH antibodies was significantly stronger than in control sections, suggesting a significant increase in PSSG amount in all grey matter neurons, particularly in motor neurons of the anterior horns, as well as in the axonal spinal tracts (mostly in posterior white columns, spinocerebellar and corticospinal tracts). These findings suggest the occurrence of oxidative stress in the spinal cord of patients with Friedreich's ataxia as a consequence of reduced frataxin expression.

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.