The neuroprotective mechanisms and effects of sulforaphane

Klomparens EA, Ding Y.; Brain Circ 2019;5:74-83 DOI: 10.4103/bc.bc_7_19

Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.

Yeast as a Tool for Deeper Understanding of Human Manganese-Related Diseases

Louise Thines, Antoine Deschamps, Jiri Stribny and Pierre Morsomme; Genes 2019, 10(7), 545; (Review) doi:10.3390/genes10070545

Several manganese-related pathologies whose molecular mechanisms have been studied in yeast are then presented in the light of the function of this cation as a non-enzymatic antioxidant or as a key cofactor of metalloenzymes. In this line, we first describe the Transmembrane protein 165-Congenital Disorder of Glycosylation (TMEM165-CDG) and Friedreich ataxia pathologies.

The path toward using microbial metabolites as therapies

Hélène C. Descamps, Beatrice Herrmann, Daphne Wiredu, Christoph A. Thaiss; EBioMedicine (Published by The Lancet), Volume 44, 2019, Pages 747-754, doi:10.1016/j.ebiom.2019.05.063.

Metabolites have emerged as the quintessential effectors mediating the impact of the commensal microbiome on human physiology, both locally at the sites of microbial colonization and systemically. The endocrine activity of the microbiome and its involvement in a multitude of complex diseases has made microbiome-modulated metabolites an attractive target for the development of new therapies.

In neurodegenerative disorders, cerebellar syndrome is thought to be related to a neurochemical deficit of 5-hydroxytryptamine (5-HT). Current clinical trials will evaluate indole-3-propionic acid supplementation, a 5-HT precursor, as a therapeutic strategy for Friedreich's ataxia and multiple sclerosis. Indole can be further converted into indoxyl and indoxyl sulfate by host hepatic oxidases (CYP2E1 and SULT1A1).

New developments in pharmacotherapy for Friedreich ataxia

Alexandra Clay, Patrick Hearle, Kim Schadt & David R. Lynch (2019) New developments in pharmacotherapy for Friedreich ataxia, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2019.1639671

Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases [version 1; peer review: awaiting peer review]

Gloria C. Ferreira, Jenna Oberstaller, Renée Fonseca, Thomas E. Keller, Swamy Rakesh Adapa, Justin Gibbons, Chengqi Wang, Xiaoming Liu, Chang Li, Minh Pham, Guy W. Dayhoff II, Linh M. Duong, Luis Tañón Reyes, Luciano Enrique Laratelli, Douglas Franz, Segun Fatumo, ATM Golam Bari, Audrey Freischel, Lindsey Fiedler, Omkar Dokur, Krishna Sharma, Deborah Cragun, Ben Busby, Rays H.Y. Jiang;  F1000Research 2019, 8:1135 Last updated: 19 JUL 2019

Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences.

Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia

Gottesfeld, J.M. Neurotherapeutics (2019). doi:10.1007/s13311-019-00764-x

Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.

Oxidative post‐translational modifications in histones

José Luis García‐Giménez, Carlos Romá‐Mateo, Federico V. Pallardó; Biofactors. 2019 Jun 11. doi: 10.1002/biof.1532.

Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox‐related epigenetic regulation. We currently face a new field of research with potential important consequences for the treatment of many pathologies.

Biointaxis busca cinco millones para culminar su fase preclínica regulatoria

La spin off del Institut Germans Trias i Pujol (Igtp) quiere levantar once millones de euros durante los próximos cinco años para desarrollar la primera solución contra la ataxia de Friedrich, una enfermedad neurodegenerativa rara.Desde la empresa aseguran que distintos fondos de capital riesgo han mostrado interés en su proyecto. Por ahora, la compañía ya ha obtenido la patente internacional para su fármaco y tiene previsto solicitar la designación de medicamento huérfano a la Agencia Europea del Medicamento (EMA, por sus siglas en inglés). De momento, Biointaxis ha levantado 300.000 euros a través de un préstamo participativo suscrito por las distintas asociaciones de pacientes que sufren ataxia de Friedrich. “Nos gusta generar un retorno a las familias que sufren la enfermedad; pensamos que incorporarlos al proyecto desde el primer momento es la mejor fórmula”, comenta Matilla. Fundada en 2018, Biointaxis es una spin off del Institut Germans Trias i Pujol (Igtp), situada en Badalona (Barcelona). La empresa surgió del trabajo conjunto entre Antoni Matilla, licenciado en Biología por la Universidad de Barcelona (UB), e Ivelisse Sánchez, del grupo de investigación en neurogenética del Igtp. La ataxia de Friedrich es una enfermedad neurodegenerativa que afecta a más de 3.000 pacientes en España El equipo también ha contado con la colaboración de Miguel Chillón, profesor en el departamento de Bioquímica y Biología Molecular de la Universitat Autònoma de Barcelona (UAB). Asimismo, el proyecto contó con el apoyo de CaixaImpulse en 2016, el programa desarrollado por la Obra Social La Caixa para asesorar a aquellas iniciativas biomédicas en etapas early stage.

The current state of biomarker research for Friedreich’s ataxia: a report from the 2018 FARA biomarker meeting

Ian A Blair, Jennifer Farmer, Steven Hersch, Jane Larkindale, David R Lynch, Jill Napierala, Marek Napierala, R Mark Payne & Sub H Subramony; Future Sci OA. 2019 Jul; 5(6): FSO398. doi:10.2144/fsoa-2019-0026

Lay abstractBiomarkers are characteristics that can be objectively measured, evaluated and used as indicators of disease progression or the effect of a therapy. Friedreich’s ataxia is a progressive multisystem neuromuscular disease with no treatment. Current clinical measures cannot robustly detect disease progression in less than a year, meaning that clinical trials are long and drug development is slow. The Friedreich’s Ataxia Research Alliance and the scientific community are looking for biomarkers that show change in shorter time frames that can accelerate drug development. The 2018 FARA Biomarker Meeting summarized the exciting findings that represent the current state of the field.

Evaluation of antibodies for western blot analysis of frataxin protein isoforms

Liwei Weng, Qingqing Wang, Sixiang Yu, Xiaolu Yang, David R. Lynch, Clementina Mesaros, Ian A. Blair; Journal of Immunological Methods,
2019, doi:10.1016/j.jim.2019.07.001.

Well-validated antibodies are required for use in western blot analysis to determine whether levels of various forms of frataxin have been increased. Here we examined the specificity of five commercially available anti-frataxin antibodies and determined whether they detect mature frataxin in mouse heart tissue. Four protein standards of monkey, human, and mouse frataxin as well as mouse heart tissue were examined using polyacrylamide gel electrophoresis (PAGE) in combination with western blot analysis.

Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells

Andy On-Tik Wong, Gabriel Wong, Michael Shen, Maggie Zi-Ying Chow, Wan Wai Tse, Bimal Gurung, Suet Yee Mak, Deborah K. Lieu, Kevin D. Costa, Camie W. Chan, Alain Martelli, Joseph F. Nabhan and Ronald A. Li; Stem Cell Research & Therapy 2019 10:203 doi:10.1186/s13287-019-1305-y

In summary, we demonstrated that the clinical symptoms of contractile and electrophysiological dysfunction in FRDA patients can be recapitulated by human cardiac tissues engineered from FXN-deficient hPSC-derived hvCMs. Translationally, the positive correlation between FXN expression and contractility and the results of our rescue experiments underscore the potential of FXN restoration by small molecules or gene therapy as an effective therapeutic strategy for suppressing or even reversing the cardiac symptoms of FRDA.

The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

Marie Beaudin, Antoni Matilla-Dueñas, Bing-Weng Soong, Jose Luiz Pedroso, Orlando G. Barsottini, Hiroshi Mitoma, Shoji Tsuji, Jeremy D. Schmahmann, Mario Manto, Guy A Rouleau, Christopher Klein, Nicolas Dupre. Cerebellum (2019). doi:10.1007/s12311-019-01052-2

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.

Seelos Therapeutics Receives Notice of Allowance for a US Patent for SLS-005 in New Indication of Friedreich Ataxia

July 02, 2019, Source: Seelos Therapeutics, Inc.

NEW YORK, July 02, 2019 (GLOBE NEWSWIRE) -- Seelos Therapeutics, Inc. (NASDAQ: SEEL), a clinical-stage biopharmaceutical company, announced today that they have received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for Seelos’ U.S. Patent Application for SLS-005 (trehalose) for treating Friedreich Ataxia (FA).

Friedreich Ataxia (FA) is a rare inherited neuromuscular disease affecting the nervous system resulting in issues with balance and coordination, spinal deformity, cardiovascular issues and in some patients can lead to the onset of diabetes. It is among the group of neurological conditions related by the commonality of protein aggregations, such as Sanfilippo syndrome, Oculopharyngeal Muscular Dystrophy (OPMD) and Huntington's disease. FA affects about one in 50,000 people worldwide, making it the most common in a group of related disorders called hereditary ataxias. More information about FA can be found at: https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/friedreichs-ataxia-fact-sheet

SLS-005 already has orphan indication for Spinocerebellar Ataxia (SCA3) and Seelos is currently developing SLS-005 for Sanfilippo syndrome followed by the OPMD indication.

Related:
Bioblast Pharma Announces Sale of its Trehalose Clinical Development Programs to Seelos Therapeutics.
Tel Aviv, Israel, Feb. 19, 2019 (GLOBE NEWSWIRE) -- Bioblast Pharma Ltd. ( Nasdaq: ORPN), a clinical-stage, orphan disease-focused biotechnology company, today announced the sale of its Trehalose clinical development programs (including its advanced phase 2 clinical program of Trehalose to treat Oculoharyngeal Muscular Dystrophy (OPMD) to Seelos Therapeutics, Inc. (Nasdaq: SEEL), a clinical-stage biopharmaceutical company.