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

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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

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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.