Sunday, November 19, 2017

Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.

Amelie Hu, Myriam Rai, Simona Donatello, Massimo Pandolfo; bioRxiv 221242; doi:10.1101/221242 (This article is a preprint and has not been peer-reviewed)
We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

Friday, November 17, 2017

Voyager Therapeutics "update"

CAMBRIDGE, Mass., Nov. 16, 2017 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases, today at its R&D Day highlighted recent progress and plans for VY-AADC for advanced Parkinson’s disease, and progress with testing novel adeno-associated virus (AAV) capsids and delivery optimization efforts, along with its ALS, Huntington’s disease, Friedreich’s ataxia, anti-Tau antibody and severe chronic pain preclinical programs.

"Preclinical data from its Friedreich’s ataxia (FA) program in a transgenic mouse model of FA, with a one-time intravenous (IV) dosing of an AAV vector composed of a novel capsid and a frataxin transgene, together with intracerebral dosing of an AAV vector with the same transgene, that led to a rapid halting and reduction of FA disease progression in multiple functional tests of motor behavior. Additional preclinical studies are underway at Voyager including steps to identify a lead clinical candidate for the treatment of FA during 2018."

Wednesday, November 15, 2017

Proactive Ethical Design for Neuroengineering, Assistive and Rehabilitation Technologies: the Cybathlon Lesson

Marcello Ienca, Reto W. Kressig, Fabrice Jotterand and Bernice Elger; ournal of NeuroEngineering and Rehabilitation 201714:115 doi:10.1186/s12984-017-0325-z

As the fields of assistive technology and neuroengineering are entering a new phase of clinical and commercial maturity, there is an increasing need to address the ethical implications associated with the design and development of novel assistive and rehabilitative technological solutions. After reviewing various ethically-sensitive approaches to the design of NART, we proposed a framework for ethical design and development, which we call the Proactive Ethical Design (PED) framework. This framework is characterized by the convergence of user-centered and value-sensitive approaches to product design through a proactive mode of ethical evaluation. Four basic normative requirements are necessary for the realization of this framework: minimization of power imbalances, compliance with biomedical ethics, translationality and social awareness.

Saturday, November 11, 2017



Tuesday, November 7, 2017

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Hong Lin, Jordi Magrane, Amy Rattelle, Anna Stepanova, Alexander Galkin, Elisia M. Clark, Yi Na Dong, Sarah M. Halawani, David R. Lynch; Disease Models & Mechanisms 2017 10: 1343-1352; doi: 10.1242/dmm.030502

Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

Sunday, November 5, 2017

Insights on the conformational dynamics of human frataxin through modifications of loop-1

Martín E. Noguera, Martín Aran, Clara Smal, Diego S. Vazquez, María Georgina Herrera, Ernesto A. Roman, Nadine Alaimo, Mariana Gallo, Javier Santos; Archives of Biochemistry and Biophysics, Available online 31 October 2017, ISSN 0003-9861, doi:10.1016/

Human frataxin (FXN) is a highly conserved mitochondrial protein involved in iron homeostasis and activation of the iron-sulfur cluster assembly. FXN deficiency causes the neurodegenerative disease Friedreich's Ataxia. Here, we investigated the effect of alterations in loop-1, a stretch presumably essential for FXN function, on the conformational stability and dynamics of the native state. We generated four loop-1 variants, carrying substitutions, insertions and deletions. All of them were stable and well-folded proteins. Fast local motions (ps-ns) and slower long-range conformational dynamics (μs-ms) were altered in some mutants as judged by NMR. Particularly, loop-1 modifications impact on the dynamics of a distant region that includes residues from the β-sheet, helix α1 and the C-terminal. Remarkably, all the mutants retain the ability to activate cysteine desulfurase, even when two of them exhibit a strong decrease in iron binding, revealing a differential sensitivity of these functional features to loop-1 perturbation. Consequently, we found that even for a small and relatively rigid protein, engineering a loop segment enables to alter conformational dynamics through a long-range effect, preserving the native-state structure and important aspects of function.

Saturday, November 4, 2017

Teaching Video NeuroImages: Spastic ataxia syndrome: The Friedreich-like phenotype of ARSACS

Saffie P, Kauffman MA, Fernandez JM, Acosta I, Espay AJ, de la Cerda A.;  Neurology. 2017 Oct;89(14) e178-e179. doi:10.1212/wnl.0000000000004556. PMID: 28972115.

ARSACS is the second most common cause of autosomal recessive spastic ataxia syndrome (SACS mutations account for 37% of Friedreich-negative cases)1 and should be considered in any population with suggestive MRI abnormalities.

Friday, November 3, 2017

BioWatch Thoughts on BioMarin's Q3-2017 Update

BioPortfolio, 30 Oct 2017 | Biotech Watcher

BMN-290 to Treat Friedreich’s Ataxia (FA)

BioMarin announced that it is advancing BMN-290 into clinical development to treat Friedreich’s Ataxia. This is a single gene disorder involving mutations in the FXN gene. This results in progressive loss of motor functions, as well as sensory impairments (i.e. vision, hearing, speech). The cognitive functions remain intact. The median age of death is around 35.

There are no FDA approved therapies. While there are “nuanced” results, the FA area clearly needs a more efficacious therapeutic in the clinical pipeline. Although BioMarin’s approach appears promising, we will reserve commentary until after the Phase 1 program is completed.

Drugs in Phase II/III Clinical Development, Friedreich’s Ataxia, October 2017

Omaveloxone (Omav), Reata Pharma (RETA), Phase 2, Nrf-2 upregulator & NF-kB inhibitor. Omav finished Part 1 of the MOXIe trial with mixed or nuanced results. 172 patient trial slated for top-line results in Q1-2020 and ongoing results until Q4-2022.

TAK-831, Takeda, Phase 2, 65 patient trial with completion slated for Q1-2019.

EPI-743, BioElectron, Phase 2, Testing patients with severe mitochondrial respiratory chain diseases who are considered to be within 90 days of end-of-life care. This includes FA patients

BMN-290 – Friedreich’s Ataxia
Small study involving chromatin modulation therapy shows promise. BMN-290 provides chromatin modulation therapy which appears more appropriate for long-term, chronic therapy. There is no disease-modifying therapy.

BMN-290 is a selective HDAC3 inhibitor of isoform 3, designed to inhibit histone deactylase enzymes. It helps unfold the chromatin structure to allow increased expression, Phase 1 - Safety Launch Q4-2017

Thursday, November 2, 2017

Personality and Neuropsychological Profiles in Friedreich Ataxia

Sabrina Sayah, Jean-Yves Rotgé, Hélène Francisque, Marcela Gargiulo, Virginie Czernecki, Damian Justo, Khadija Lahlou-Laforet, Valérie Hahn, Massimo Pandolfo, Antoine Pelissolo, Philippe Fossati, Alexandra Durr; Cerebellum (2017). doi:10.1007/s12311-017-0890-5

We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.

Wednesday, November 1, 2017

First Gene Therapy Treatment Candidate to Receive Orphan Designation in EU and USA

Agilis Biotherapeutics Announces Orphan Product Designation Approval in Europe for the Treatment of Friedreich Ataxia.

CAMBRIDGE, Mass.--(BUSINESS WIRE), October 31, 2017; Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the European Commission (EC) has granted Orphan Medicinal Product (OMP) designation in the European Union (EU) to the Company’s gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich ataxia (FA), an inherited degenerative neuromuscular disorder resulting in loss of motor coordination and strength, hearing, vision, speech and often premature death. The EC’s approval follows a positive opinion in July 2017 from the European Medicine Agency’s (EMA) Committee for Orphan Medicinal Products (COMP). This follows the Orphan Drug Designation for AGIL-FA granted by the U.S. Food and Drug Administration (FDA) last year.