Friedreich Ataxia: Treatment with Genetic Approach

Martin L. Nelwan, Journal of Advances in Biology & Biotechnology, 2394-1081,Vol.: 14, Issue.: 4

Adequate treatments are unavailable for this disorder at present. However, to treat FA, genetic approach can be used. The approach may comprise genetic counseling and use of advanced therapy, gene therapy for instance. 

Molecular Alterations in a Mouse Cardiac Model of Friedreich’s Ataxia: An Impaired Nrf2 Response Mediated via Up-Regulation of Keap1 and Activation of the Gsk3β Axis

Amy Anzovino, Shannon Chiang, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang, The American Journal of Pathology, Available online 19 September 2017, ISSN 0002-9440,  doi:10.1016/j.ajpath.2017.08.021.

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich’s ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms.
Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

Movement disorders hidden in the neuromuscular clinic

J. Reimann, S. Paus, Neuromuscular Disorders, Volume 27, Supplement 2, October 2017, Page S243, ISSN 0960-8966, doi:10.1016/j.nmd.2017.06.531.

We present these exemplary cases to increase awareness of these disorders and the differential diagnosis for those working in neuromuscular clinics, as well as an incentive for more interaction with the movement disorder field, in particular when struggling to define a diagnosis. We also observe a number of referrals that turn out to be movement disorders. In some, this is caused by known neuromuscular manifestations while missing the CNS signs. Examples are our cases of Huntington’s disease presenting with weakness, pain and atrophy of the calves and of Friedreich ataxia send for work-up of sensory axonal neuropathy and scoliosis, where “restlessness” and “nasal speech”, respectively, were ignored as symptoms. In others, the attribution of the pathophysiology to muscle is simply wrong.

Relationship Between Neurological Disability and Visual Impairment in Patients With ALS or Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT03285204, First received: March 8, 2017
Principal Investigator: Jose L Urcelay, PhD HGU Gregorio Marañón.
Location: Madrid, Spain,

The aim of this study is to obtain an early biomarker of amyotrophic lateral sclerosis and Friedreich's Ataxia which allows to diagnose the disease in an initial stage and to follow up the patient with optic coherence tomography, a fast, non-invasive and comfortable method.

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu, In Progress in Neurobiology, Volume 157, 2017, Pages 273-291, ISSN 0301-0082, doi:10.1016/j.pneurobio.2015.10.005.

Highlights:
Reprogramming energetic metabolism is a common feature for neurodegenerative diseases and cancers.
Methylene blue functions as an alternative mitochondrial electron transfer carrier, enhancing bioenergetics and inhibiting biosynthetics.
Methylene blue provides protective effect in rodent models of Parkinson disease, Alzheimer's disease, Huntington's disease, and Friedreich's ataxia.
Methylene blue reverses Warburg's effect and inhibits cancers proliferation.
Alternative mitochondrial electron transfer may provide a common novel therapeutic mechanism for cancers and neurodegenerative diseases.

Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations

S Simoens and I Huys; Gene Therapy , (7 September 2017) | doi:10.1038/gt.2017.79

In December 2016, Spinraza (Nusinersen), Biogen (Durham, NC, USA) was the first treatment to be registered as an orphan drug by the US Food and Drug Administration for SMA. In Europe, a gene therapy in principle classifies as an Advanced Therapy Medicinal Product (ATMP), covered by a regulatory framework with particular incentives for drug developers. For Nusinersen, the European Medicines Agency recently granted the Accelerated Assessment status in 2016. With respect to its price, it has been reported that the annual wholesale costs of treating a patient with Nusinersen will amount to $750 000 for the first year and $375 000 for subsequent years. Biogen argues that this price is in line with that of other orphan drugs for rare diseases.
Despite marketing authorization of Nusinersen in the United States and in Europe, patient access to this new promising therapy remains uncertain. The price of this new drug clearly triggers several questions in terms of justification, transparency and responsibility.
The aim of this Comment is to identify and to discuss issues related to the market access of Nusinersen for SMA by focusing specifically on intellectual property rights, pricing, value and coverage considerations from the perspective of the company, patients and society.
The pricing of Nusinersen is a black box, although Biogen claims that the price of Nusinersen is in line with its clinical benefit and with prices of other orphan drugs. Any data about the value assessment of Nusinersen is not (publicly)available. This asymmetry (or even absence) of information between Biogen and insurers needs to be tackled in an era when insurers (and society at large) need to make and justify difficult choices. A quantifiable and evidence-driven approach to pricing and value assessment is required and such data need to be available to the stakeholders involved.

Detection of long repeat expansions from PCR-free whole-genome sequence data

Egor Dolzhenko, Joke J.F.A. van Vugt, Richard J. Shaw, Mitchell A. Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S. Ajay, Vani Rajan, Bryan Lajoie, Nathan H. Johnson, Zoya Kingsbury, Sean J. Humphray, Raymond D. Schellevis, William J. Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H.P. Tazelaar, Michael A. van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J. Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S. Wexler, The US-Venezuela Collaborative Research Group, David E. Housman, Christopher W. Ng, Alina L. Li, Ryan J. Taft, Leonard H. van den Berg, David R. Bentley, Jan H. Veldink, and Michael A. Eberle. Genome Res. gr. 225672.117 Published in Advance September 8, 2017, doi:10.1101/gr.225672.117

We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.

Nitric oxide prevents Aft1 activation and metabolic remodeling in Frataxin-deficient yeast

David Alsina, Joaquim Ros, Jordi Tamarit, Redox Biology, Available online 6 September 2017, ISSN 2213-2317, doi:10.1016/j.redox.2017.09.001.






A major conclusion of this work is that Yfh1 deficiency activates the iron regulon by a different pathway than iron-sulfur loss. Therefore, alternative pathways for Aft1 activation may exist in yeast which, as discussed above, could be related to the presence of anomalous iron species. We have also observed that metabolic status can be efficiently monitored using a targeted proteomics strategy focusing on key metabolic enzymes. Finally, the observation that NO can mitigate the defects caused by Yfh1 deficiency supports the hypothesis that Yfh1 loss leads to the increased presence of anomalous iron forms, and that this anomalous iron plays a central role in the events caused by Yfh1 deficiency. It also suggests that NO donors could have a therapeutic effect in FRDA patients. NO donors such as SNP or nitroglycerin have been used for more than a century for controlling congestive heart failure associated with heart attack or lowering blood pressure during surgery. Beyond its vasodilating action, neuroprotective properties have been demonstrated for NO in an iron-induced model of Parkinson's disease. This observation, together with the results presented in this work, opens the possibility to explore the potential therapeutic effect of NO donors in mammalian models of FRDA.

RNA biology of disease-associated microsatellite repeat expansions

Kushal J. Rohilla and Keith T. Gagnon, Acta Neuropathologica 20175:63, doi:10.1186/s40478-017-0468-y

This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.
Repeat expansion sequences are known to inhibit or impede RNA Polymerase II (Pol II) initiation or elongation either directly or via induction of a repressed chromatin state. Expansions like the GAA repeat in FRDA have been implicated in reduced or silenced transcription.
Examples of microsatellite repeat expansions modulating splicing include the GAA repeat expansion associated with FRDA. When placed near reporter gene exons or in the first intron of a frataxin minigene system, the GAA repeat caused complex splicing defects and accumulation of aberrant splice products. The mechanism proposed involved binding of various splicing factors to the GAA repeat-containing transcripts.
Therapeutic approaches to control xtrRNA transcription and splicing:
Characterizing the effect of microsatellite expansions on transcription and splicing will directly benefit therapeutic approaches for repeat expansion disorders. Proof-of-principle methods to locally disrupt the interactions of xtrRNA at repeat expansion loci, such as R-loops, have been demonstrated for FXS and FRDA using small molecules and nucleic acids.
For splicing-based therapeutics, blocking inclusion of repeat expansion-containing introns, such as with splice-modulating antisense oligonucleotides or small RNAs, could prove to be useful for disorders like FRDA and C9FTD/ALS.
With the emergence of gene editing technologies, the direct removal of repeat expansions from the genome may also be possible. Removal of genomic repeat expansions could eliminate the possibility of xtrRNA expression or reverse repressive epigenetic states.While potential CRISPR-based therapeutics are exciting, precautions must be taken to address potential pitfalls and challenges like off-target effects, delivery, and cell-type specific mechanisms of DNA damage repair

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

Ryan J. McGinty, Franco Puleo, Anna Y. Aksenova, Julia A. Hisey, Alexander A. Shishkin, Erika L. Pearson, Eric T. Wang, David E. Housman, Claire Moore, Sergei M. Mirkin, Cell Reports, Volume 20, Issue 10, 5 September 2017, Pages 2490-2500, ISSN 2211-1247, doi:10.1016/j.celrep.2017.08.051