Pharmacological treatments for Friedreich ataxia

Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M. Pharmacological treatments for Friedreich ataxia. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD007791. DOI: 10.1002/14651858.CD007791.pub4.

Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability

Arnaud Chevalier, Mohammad Parvez Alam, Omar M. Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney M. Hecht,Bioorganic & Medicinal Chemistry, Available online 23 August 2016, ISSN 0968-0896, doi:10.1016/j.bmc.2016.08.039.

The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.

Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia

Marissa Z. McMackin, Chelsea K. Henderson, Gino A. Cortopassi, Behavioural Brain Research SreeTestContent1 SreeTestContent1, Available online 26 August 2016, ISSN 0166-4328, doi:/10.1016/j.bbr.2016.08.053.

The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

Benjamí Oller-Salvia, Macarena Sánchez-Navarro, Ernest Giralt and Meritxell Teixidó, (Review Article) Chem. Soc. Rev., 2016, 45, 4690-4707 DOI: 10.1039/C6CS00076B

Open Access Article

Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.

Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.

Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.

CONTINUUM: Lifelong Learning in Neurology

Ashizawa, Tetsuo MD, FAAN; Xia, Guangbin MD, PhD; August 2016 - Volume 22 - Issue 4, Movement Disorders - p 1208–1226 doi: 10.1212/CON.0000000000000362

Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.

Movement disorders in mitochondrial diseases

Tranchant, Anheim. Rev Neurol (Paris). 2016 Jul 28. pii: S0035-3787(16)30025-X. doi: 10.1016/j.neurol.2016.07.003.

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns–Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function.

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Nishaki Mehta, Paul Chacko, James Jin, Tam Tran, Thomas W. Prior, Xin He, Gunjan Agarwal, and Subha V. Raman (2016). Texas Heart Institute Journal: August 2016, Vol. 43, No. 4, pp. 305-310.
doi:10.14503/THIJ-14-4198

We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.

Tech giants moving into health may widen inequalities and harm research, unless people can access and share their data, warn John T. Wilbanks and Eric J. Topol.

John T. Wilbanks & Eric J. Topol, Nature 535, 345–348 (21 July 2016) doi:10.1038/535345a

Nature-Comment OPEN

Citizens worldwide have too long a history of being passive players in health care — blindly following instructions from providers. And studies that have tracked reactions to revelations about global surveillance programmes suggest that most people are resigned to the idea that ownership and control of personal information is incompatible with the Internet age.

Yet just as social networking has rocketed around the world in a decade, a worldwide knowledge resource could soon be used to identify the best course of treatment for an individual on the basis of the experiences of millions. This resource will never be built unless each of us takes responsibility for our own health and disease, and for the information that we can generate about ourselves. When it comes to control over our own data, health data must be where we draw the line.

Drug screening: Drug repositioning needs a rethink

Xianting Ding, Nature 535, 355 (21 July 2016) doi:10.1038/535355d  Published online 20 July 2016

Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones. Disease is often an integration of multiple pathologies, so these are potentially treatable with different drug combinations that act in synergy.

For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.

Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: the IMAGE-FRDA study.

Selvadurai LP , Harding IH , Corben LA , Stagnitti MR , Storey E , Egan GF , Delatycki MB , Georgiou-Karistianis N
J Neurol [2016] doi:10.1007/s00415-016-8252-7

This study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Rowena Schultz; Otto W. Witte; Christian Schmeer; Investigative Ophthalmology & Visual Science August 2016, Vol.57, 4115-4124. doi:10.1167/iovs.16-19260
OPEEN ACCES This work is licensed under a Creative Commons 

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Khonsari H , Schneider M , Al-Mahdawi S , Chianea YG , Themis M , Parris C , Pook MA , Themis M; Gene Therapy accepted article preview 12 August 2016; doi: 10.1038/gt.2016.61

Open

Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's Ataxia

Emanuela Piermarini, Daniele Cartelli, Anna Pastore, Giulia Tozzi, Claudia Compagnucci, Ezio Giorda, Jessica D’Amico, Stefania Petrini, Enrico Bertini E, Graziella Cappelletti and Fiorella Piemonte, Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw260, First published online: August 11, 2016

We hypothesize that oxidative stress, determined by high GSSG levels, induces axonal retraction by interfering with MT dynamics. We propose a mechanism of the axonopathy in FRDA where GSSG overload and MT de-polymerization are strictly interconnected. Indeed, using a frataxin-silenced neuronal model we show a significant reduction of neurites extension, a shift of tubulin toward the unpolymerized fraction and a consistent increase of glutathione bound to the cytoskeleton.

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Oleksandr Gakh, Wasantha Ranatunga, Douglas Y. Smith IV, Eva-Christina Ahlgren, Salam Al-Karadaghi, James R. Thompson and Grazia Isaya. JBC, First Published on August 12, 2016 doi: 10.1074/jbc.M116.738542

Characterization of Novel Small-Molecule NRF2 Activators: Structural and Biochemical Validation of Stereospecific KEAP1 Binding

Carlos Huerta, Xin Jiang, Isaac Trevino, Christopher F. Bender, Deborah A. Ferguson, Brandon Probst, Kerren K. Swinger, Vincent S. Stoll, Philip J. Thomas, Irina Dulubova, Melean Visnick, W. Christian Wigley, Biochimica et Biophysica Acta (BBA) - General Subjects, Available online 27 July 2016, ISSN 0304-4165, doi:10.1016/j.bbagen.2016.07.026.

Clinical trials of omaveloxolone are currently underway in several indications, including Friedreich’s Ataxia, mitochondrial myopathies, corneal endothelial cell loss following cataract surgery, and melanoma. The increased risk for acute fluid overload adverse events observed in BEACON with late-stage CKD patients has not been observed in subsequent studies with bardoxolone methyl or omaveloxolone.

Synthetic Nucleic Acids and Treatment of Neurological Diseases

David R. Corey, PhD, JAMA Neurol. Published online August 01, 2016. doi:10.1001/jamaneurol.2016.2089

OPEN

EMERGING TARGET: FRATAXIN/FRIEDREICH’S ATAXIA

Friedreich’s ataxia is a multiorgan disease that affects the central nervous system, heart, pancreas, and other diseases.25 Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system. Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.

 The expanded RNA binds to chromosomal DNA to form an R-loop. This R-loop induces histone modifications and reduces transcription. The antisense oligonucleotide binds the expanded repeat, prevents the RNA from binding to the DNA, and releases the break on transcription. The expression of FXN increases to normal levels.


Further testing of anti-AAG oligonucleotides will focus on generalizing the findings to a wider variety of patient-derived cell lines with various numbers of repeats. In the longer term, preclinical and clinical testing will likely benefit from the lessons learned developing nucleic acid drugs for the treatment of other diseases.

Variable sensory nerve conduction parameters in late onset Friedreich ataxia

Alix, J. J.P., Alam, T., Garrard, K., Martindale, J., Shanmugarajah, P., Rao, D. G. and Hadjivassiliou, M. (2016). Muscle Nerve. Accepted Author Manuscript. doi:10.1002/mus.25363

Overall, in LOFA, S-NCS may be variable, and clinicians should consider genetic testing in patients with late onset ataxia and normal nerve conduction studies.

Long-Axis Left Ventricular and Left Atrial Dysfunction in Friedreich Ataxia with Normal Ejection Fraction – Global Longitudinal Strain Versus Tissue Doppler Imaging Velocities

D. Jackson, R. Hassam, L. Donelan, R. Peverill, Heart, Lung and Circulation, Volume 25, Supplement 2, August 2016, Page S80, ISSN 1443-9506, http://dx.doi.org/10.1016/j.hlc.2016.06.185.

In FRDA there are complex interrelationships between global longitudinal strain and tissue Doppler imaging mitral annular velocities, but the strongest correlate of the severity of the genetic abnormality (GAA1) is atrial contraction.

Translating HDAC inhibitors in Friedreich’s ataxia

Elisabetta Soragni & Joel M. Gottesfeld. Expert Opinion on Orphan Drugs, Published online: 31 Jul 2016 DOI:10.1080/21678707.2016.1215910

Expert opinion: 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing

Voice in Friedreich Ataxia

Adam P. Vogel, Mayumi I. Wardrop, Joanne E. Folker, Matthis Synofzik, Louise A. Corben, Martin B. Delatycki, Shaheen N. Awan, Journal of Voice, Available online 5 August 2016, ISSN 0892-199 doi:10.1016/j.jvoice.2016.04.015.

Objective: To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy.

Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy.

 Treatments designed to improve communicative function should consider therapeutic approaches that aim to improve phonatory stability (eg, use of increased respiratory support prior to the initiation of voicing), and thereby improve vocal pitch and quality control. In addition, therapeutic methods that aid the patient in increasing rate of speech may also be of benefit.

The Pediatric Cerebellum in Inherited Neurodegenerative Disorders: A Pattern-recognition Approach

Susan I. Blaser, Maja Steinlin, Almundher Al-Maawali, Grace Yoon, Neuroimaging Clinics of North America, Volume 26, Issue 3, August 2016, Pages 373-416, ISSN 1052-5149, doi:10.1016/j.nic.2016.03.007.

FRIEDREICH ATAXIA IS THE PROTOTYPE FOR NEURODEGENERATIVE DISORDERS WITH PREDOMINANT SPINAL CORD ATROPHY:
Assessment of the upper cervical cord is predominantly useful in the evaluation of patients with Friedreich ataxia (FRDA/FXN), in whom cord thinning caused by neuronal loss in the spinal ganglia and Clarke column may be the first imaging clue to the disorder.
Involvement of the cerebellum was initially considered a rare feature in FRDA, however, volumetric analysis of the cerebellum in FRDA confirms volume loss in the rostral vermis, dorsal medulla, the dentate nuclei, the peridentate white matter, and the associated superior cerebellar peduncle.

Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia

Antonio Costantini, Tiziana Laureti, Maria Immacolata Pala, Marco Colangeli, Simona Cavalieri, Elisa Pozzi, Alfredo Brusco, Sandro Salvarani, Carlo Serrati, Roberto Fancellu. Original Communication, Journal of Neurology pp 1-9, First online: 03 August 2016. DOI: 10.1007/s00415-016-8244-7

Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine.

Agilis Biotherapeutics Announces FDA Orphan Drug Designation for the Treatment of Friedreich’s Ataxia (FA)

August 02, 2016 08:30 AM Eastern Daylight Time. August 02, 2016.

First Gene Therapy Candidate to Receive Designation for FA.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to Agilis’ gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich’s ataxia (FA).

Pfizer buys gene therapy company - Is it a good investment?

Rare Disease Report. James Radke, PhD, Published Online: Monday, Aug 01, 2016

Pfizer has acquired gene therapy company Bamboo Therapeutics for a deal that could be worth up to $645 million.
Bamboo therapeutics is developing gene therapy for Giant Axonal Neuropathy (GAN) that is currently in phase 1/2 trial. The company also has gene therapies in development for 3 other neuromuscular diseases – Duchenne muscular dystrophy, Canavan, and Friedreich’s ataxia.

Recent advances in understanding transcription termination by RNA polymerase II.

Travis J. Loya and Daniel Reinesa,  F1000Research 2016, 5(F1000 Faculty Rev):1478  doi: 10.12688/f1000research.8455.1

R-loop-mediated termination is also proposed to play a role in Friedrich’s ataxia. It was suggested that R-loops aberrantly form in the frataxin gene as a result of expansion of GAA repeats in its first intron 58, 59. Mutated frataxin exhibits features of heterochromatin, H3K9 methylation, and decreased acetylation of H3 and H4, thus a reduced level of expression is to be expected. However, the altered gene also shares many characteristics of canonical R-loop-terminated genes, including a polyA-signal-like sequence upstream of the expansion, followed by a GU-rich sequence similar to the downstream element of polyA signals. This has led to a proposal that the mutated frataxin allele is the victim of premature termination, which contributes to its low level of expression in patients. While experimental verification is still needed, this is an interesting model for a role of termination in disease.