Saturday, July 22, 2017

Pharmacological therapeutics in Friedreich Ataxia: The present state

Cassandra Strawser, Kimberly Schadt, Lauren Hauser, Ashley McCormick, Mckenzie Wells, Jane Larkindale, Hong Lin & David R Lynch; Expert Review of Neurotherapeutics Vol. 0 , Iss. ja,0, Accepted author version posted online: 20 Jul 2017 doi: 10.1080/14737175.2017.1356721

Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.

Friday, July 21, 2017

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Angelical S. Martin, Dennis M. Abraham, Kathleen A. Hershberger, Dhaval P. Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J. Muehlbauer, Paul A. Grimsrud, Jason W. Locasale, R. Mark Payne, and Matthew D. Hirschey, JCI Insight. 2017;2(14):e93885. doi: 10.1172/jci.insight.93885.

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. Our data define a clear role for SIRT3 in mediating the beneficial effects of NMN in this HF model; thus, future studies in the FXN-KO and dKO models would be of interest to evaluate the consequences of manipulating of redox-induced acetylation versus SIRT3-regulated acetylation. These studies include studies dedicated to varying the NMN dosing regimen, as well as acetyl-proteomic analysis of hearts from these NMN-treated mice. Our findings presented here serve as important preclinical data to highlight NMN supplementation and/or SIRT3 agonist treatment as potential therapeutic strategies in FRDA patients and HF.

Wednesday, July 19, 2017

Interrogating the “unsequenceable” genomic trinucleotide repeat disorders by long-read sequencing

Qian Liu, Peng Zhang, Depeng Wang, Weihong Gu and Kai Wang; Genome Medicine 20179:65 DOI: 10.1186/s13073-017-0456-7

Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably.

In this study, we have developed RepeatHMM to detect repeat counts of microsatellites from long-read sequencing data. RepeatHMM was evaluated on both simulation data and real data and our results suggested that RepeatHMM was effective and efficient to quantify repeat counts. RepeatHMM is flexible to handle repeat patterns of any length beyond trinucleotide repeats and can incorporate different error profiles. With the wider application of long-read sequencing techniques in research and clinical settings, RepeatHMM is expected to contribute to the quantification of repeat counts and to facilitate the analysis of genotype-phenotype relationships for disease-related microsatellites.

Wednesday, July 12, 2017

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients

M. Seco-Cervera, D. González-Rodríguez, J. S. Ibáñez-Cabellos, L. Peiró-Chova, P. González-Cabo, E. García-López, J. J. Vílchez, I. Sanz-Gallego, F. V. Pallardó & J. L. García-Giménez; Scientific Reports 7, Article number: 5237 (2017) doi:10.1038/s41598-017-04996-9

miR-323a-3p as a biomarker for diagnosis of cardiomyopathy in FRDA

Circulating miRNAs can detect pathological events, and could also monitor molecular signals participating in cardiomyopathy even before the appearance of clinical cardiac manifestations. To maximize the likelihood of detecting the onset or progression of cardiomyopathy, we suggest combining standard cardiac diagnostic procedures with the use of circulating microRNAs. This approach could provide more clinical information for evaluating cardiomyopathy progression in FRDA. In summary, miRNAs obtained in this study show new candidates for personalized therapy in FRDA patients.

Tuesday, July 11, 2017

How does performance of the Friedreich Ataxia Functional Composite compare to rating scales?

Geneieve Tai, Eppie M. Yiu, Martin B. Delatycki, Louise A. Corben; J Neurol (2017). doi:10.1007/s00415-017-8566-0

The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components.

Sunday, July 9, 2017

Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity

Pablo Calap-Quintana, Javier González-Fernández, Noelia Sebastiá-Ortega, José Vicente Llorens, Orcid and María Dolores Moltó; Int. J. Mol. Sci. 2017, 18(7), 1456; doi:10.3390/ijms18071456

Drosophila models of FRDA support the proposal that iron plays a major role in FRDA physio-pathology. Although reduction in iron levels by iron chelation has been relatively successful in clinical trials, genetic or pharmacological intervention through the sphingolipid/Pdk1/Mef-2 pathway and pathways regulating iron homeostasis are new approaches to be explored in preclinical studies.

Wednesday, July 5, 2017

Selected missense mutations impair frataxin processing in Friedreich ataxia

Elisia Clark, Jill S. Butler, Charles J. Isaacs, Marek Napierela and David R. Lynch; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.433

FXNI154F and FXNG130V missense mutations decrease FXN81–210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.

Thursday, June 29, 2017

Friedreich’s ataxia associated with marfanoid features & alopecia areata-rare disease manifestations or chance association?

Chandramohan Sharma, Banshilal Kumawat, Maulik Panchal, Kaushik Rana, Indian Journal of Medical Specialities, Available online 19 June 2017, ISSN 0976-2884, doi:10.1016/j.injms.2017.06.005.

Apart from neurological features it has cardiac, skeletal and endocrine manifestations but its association with marfanoid features and/or alopecia areata have not been described in literature.

Wednesday, June 28, 2017

Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences

Berntsson SG, Landtblom A-M, Flensner G; PLoS ONE 12(6): e0180054.

Elucidating patients´ experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants’ experiences through semi-structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants’ personal life, employment, and daily activities. The participants’ experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief.

Thursday, June 22, 2017

Reata Pharmaceuticals, Inc. Receives Orphan Drug Designation For Omaveloxolone For The Treatment Of Friedreich’s Ataxia

RVING, Texas, June 22, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to omaveloxolone for the treatment of Friedreich’s ataxia.
"Orphan drug designation serves as an important milestone for our company as it recognizes the promise of omaveloxolone as a potential new treatment for FA. In light of the recent, encouraging clinical data, we are hopeful that omaveloxolone will be the first therapy approved for patients with FA," said Warren Huff, Chief Executive Officer of Reata.