The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients.

Rodrigues, Miriam J., O’Grady, Gina, Hammond-Tooke, Graemed, Kidd, Alexaf, Love, Donald O.g, Baker, Ronelle K.b, Roxburgh, Richard H.a; Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 183-188, 2017; DOI: 10.3233/JND-170240

The changing roles of a rare disease patient registry. (a) Ten roles performed by registries along the pathway of treatment development – adapted with permission from Betsy Bogard (see acknowledgements*). (b) The NZ NMD Registry’s current role in the pathway of treatment development for its respective patient populations.

We have demonstrated that an overarching registry serving all neuromuscular diseases managed by a single project team is effective; this is in contrast to countries such as the UK, Spain and Germany where disease-specific registries are commonly deployed but similar to Canada where the Canadian Neuromuscular Disease Registry (CNDR) covers a range of disorders

Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone

Arnulf H. Koeppen, MD Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhD Joseph E. Mazurkiewicz, PhD; Journal of Neuropathology & Experimental Neurology, nlx087, doi:10.1093/jnen/nlx087

The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Agilis Biotherapeutics Updates on Progress in CNS Gene Therapy Programs

CAMBRIDGE, Mass.--(October 03, 2017)--Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS),

Friedreich Ataxia: The Company’s program in Friedreich ataxia (FA), AGIL-FA, an AAV-based vector for delivery of the human FXN gene intended to address the CNS manifestations of FA, is advancing rapidly through nonclinical, manufacturing and regulatory activities toward human clinical study. Agilis has generated a proprietary library of optimized FXN gene constructs through engineering of promotor and gene regulatory elements tied to the wild-type FXN gene in collaboration with Intrexon Corporation (NASDAQ: XON), resulting in novel compositions of matter and intellectual property. In vitro characterization, including analyses in inducible pluripotent stem cell systems, has verified the critical functional parameters of the optimized FXN gene and frataxin protein, leading to selection of the AGIL-FA lead construct. Analyses of routes of CNS administration and biodistribution of the optimized lead construct using the selected AAV vector have been completed in five in vivo IND-enabling non-clinical studies, demonstrating reproducible targeting of the FXN gene to, and expression of the frataxin protein in, target CNS cells that data suggest are integral to CNS manifestations in FA. The Company has completed a pre-IND meeting with the FDA and is on track to open an IND in 2018

Comprehensive Analysis of Gene Expression Patterns in Friedreich’s Ataxia Fibroblasts by RNA Sequencing Reveals Altered Levels of Protein Synthesis Factors and Solute Carriers

Napierala JS, Li Y, Lu Y, Lin K, Hauser LA, Lynch DR, Napierala M; University of Alabama at Birmingham, Accession: PRJNA412241, National Center for Biotechnology Information, GEO: the Gene Expression Omnibus. Public on Sep 27, 2017

We used RNA sequencing to profile the transcriptomes of primary fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Transcriptome profiling of FRDA skin fibroblasts revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in the FRDA cells. Finally, comparison of genes differentially expressed in FRDA fibroblasts to 3 previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease.

Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment

Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros; J. Cell. Mol. Med. Vol XX, No X, 2017 pp. 1-15 doi: 10.1111/jcmm.13365

In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia.

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population

Jonathan F. Plehn, Keren Hasbani, Inez Ernst, Kenneth D. Horton, Bart E. Drinkard, Nicholas A. Di Prospero, Journal of Cardiac Failure, Available online 3 October 2017, ISSN 1071-9164, doi:10.1016/j.cardfail.2017.09.012.

A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.
In our pediatric cohort, GAA repeat length on either allele failed to correlate with LVMI or with measures of systolic or diastolic LV function. These findings are consistent with those of others, two or which were based on robust cMRI criteria. We did note a non-significant trend in GAA repeat length on the long allele with increasing categorical severity of LV remodeling. Despite the high prevalence of ventricular remodeling and functional associations described in this population, there is no evidence to date that early pharmacologic intervention can prevent or impede development of ventricular and/or clinical deterioration.

Urinary, bowel and sexual symptoms in a cohort of patients with Friedreich’s ataxia

Meher Lad, Michael H. Parkinson, Myriam Rai, Massimo Pandolfo, Petya Bogdanova-Mihaylova, Richard A. Walsh, Sinéad Murphy, Anton Emmanuel, Jalesh Panicker† and Paola Giunti; Orphanet Journal of Rare Diseases 201712:158 doi:10.1186/s13023-017-0709-y

Pelvic symptoms are distressing symptoms experienced by patients with Friedreich’s Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA.
A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Brian Feingold, William T. Mahle, Scott Auerbach, Paula Clemens, Andrea A. Domenighetti, John L. Jefferies, Daniel P. Judge, Ashwin K. Lal, Larry W. Markham, W. James Parks, Takeshi Tsuda, Paul J. Wang, Shi-Joon Yoo
and On behalf of the American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council; Circulation. 2017;136:e200-e231 doi:10.1161/CIR.0000000000000526

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions.
Cardiac manifestations consist of LV hypertrophy with fibrosis and scarring, arrhythmias, and progressive HF. Cardiac dysfunction is the most frequent cause of death in FA.
Because no relationship between severity of cardiac involvement and neurological status has been identified, regular cardiac evaluation regardless of neurological status is likely warranted.

Diabetes mellitus as the presenting feature of Friedreich's ataxia

Garg M, Kulkarni SD, Shah KN, Hegde AU. J Neurosci Rural Pract 2017;8, Suppl S1:117-9 DOI: 10.4103/jnrp.jnrp_112_17

This is an unusual report of diabetes as the initial presentation in a patient with FA. This patient has also shown accelerated course of disease. However, the genetic mechanisms accounting for phenotypic variations in FA remain to be fully elucidated. In patients with diabetes who present with early sensory neuropathy or ataxia, FA should be a consideration even in the pediatric age group. A better understanding of molecular mechanisms will certainly pave the way for improved therapeutic strategies in the near future.

Lipophilic methylene violet analogues as modulators of mitochondrial function and dysfunction

Sandipan Roy Chowdhury, Omar M. Khdour, Indrajit Bandyopadhyay, Sidney M. Hecht. In Bioorganic & Medicinal Chemistry, 2017,ISSN 0968-0896, doi:10.1016/j.bmc.2017.08.021.

The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich’s ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.

Keywords: Methylene blue; Methylene violet; Mitochondria; Reactive oxygen species; Friedreich’s ataxia; Cytoprotection