Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort

Emily Xiong, Abigail E. Lynch, Louise A. Corben, Martin B. Delatycki, S.H. Subramony, Khalaf Bushara, Christopher M. Gomez, J. Chad Hoyle, Grace Yoon, Bernard Ravina, Katherine D. Mathews, George Wilmot, Theresa Zesiewicz, M. Susan Perlman, Jennifer M. Farmer, Christian Rummey, David R. Lynch; Neurological Sciences, Volume 0, Issue 0, 116642 DOI:10.1016/j.jns.2019.116642

The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.

Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, and Miriam Cnop; JCI Insight. Published December 26, 2019. doi:10.1172/jci.insight.134221.

Antioxidant-mediated protective role of Hericium erinaceus (Bull.: Fr.) Pers. against oxidative damage in fibroblasts from Friedreich’s ataxia patient

LEW, Sze-Yuen; YOW, Yoon-Yen; LIM, Lee-Wei; WONG, Kah-Hui; SciELO journals. Dataset doi:10.6084/m9.figshare.11390835.v1

In this study, we investigated the antioxidant activities of a standardized aqueous extract from fruiting bodies of Hericium erinaceus mushroom (HESAE) and its protective effects against oxidative damage induced by L-Buthionine sulfoximine (BSO) in fibroblasts derived from FRDA patient. The lactate dehydrogenase-based viability assay showed that FRDA fibroblast was sensitive to 12.5 mM BSO with a reduction of viability to 52.51 ± 13.92% after 24 h of BSO exposure. Interestingly, co-incubation with 32 mg/mL HESAE increased the viability to 85.35 ± 3.4%. Further, 12.5 mM BSO caused a decrease in the ratio of cellular reduced glutathione (GSH) to oxidised GSH (GSSG) that leads to cell death.

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Rating scales for rare neurological diseases

Massimo Pandolfo; Neurol Genet Dec 2019, 5 (6) e380; DOI: 10.1212/NXG.0000000000000380

While only future experience will establish whether these scales are equally effective in FRDA clinical trials or if one proves superior, the point that they are both ataxia rating scales rather than comprehensive assessments of all FRDA neurologic features remains. Can we generalize this conclusion and say that rating scales assessing specific neurologic features are to be preferred to disease-specific scales in rare neurologic disorders? This is an open and controversial question. There have been and there are continuing efforts to develop and validate disease-specific scales for rare and even ultra-rare diseases, with the goal of disposing of robust, sensitive outcome measures for clinical trials, capturing as much as possible of the complexities of each of these conditions. Whether the same goal can be attained by appropriately combining general scales for neurologic impairments as weakness, spasticity, ataxia, and dystonia remains to be determined, but, in the light of our experience with a disease with as complex a neurologic picture as FRDA, this approach may be a viable and possibly even a preferable option.

Nanoscopic X‐ray imaging and quantification of the iron cellular architecture within single fibroblasts of Friedreich's ataxia patients

De Samber, B., Vanden Berghe, T., Meul, E., Bauters, S., Seyrich, M., Smet, J., De Paepe, B., da Silva, J.C., Bohic, S., Cloetens, P., Van Coster, R., Vandenabeele, P. and Vincze, L. (2020), J. Synchrotron Rad.. doi:10.1107/S1600577519015510

Here the nanoscale iron distribution within single fibroblasts from FRDA patients was investigated using synchrotron‐radiation‐based nanoscopic X‐ray fluorescence and X‐ray in‐line holography at the ID16A nano‐imaging beamline of the ESRF.
Various micrometre‐sized iron‐rich organelles could be revealed for the first time, tentatively identified as endoplasmic reticulum, mitochondria and lysosomes. Also a multitude of nanoscopic iron hot‐spots were observed in the cytosol, interpreted as chaperoned iron within the fibroblast's labile iron pool. These observations enable new hypotheses on the storage and trafficking of iron in the cell and ultimately to a better understanding of iron‐storage diseases such as Friedreich's ataxia.

Age of onset determines intrinsic functional brain architecture in Friedreich ataxia

Naeije, G., Wens, V., Coquelet, N., Sjøgård, M., Goldman, S., Pandolfo, M. and De Tiège, X.P. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50966

Age of symptoms onset is a major determinant of FRDA patients' intrinsic functional brain architecture. Higher rsFC in FRDA patients with later age of symptoms onset supports compensatory mechanisms for FRDA‐related neural network dysfunction and position neuromagnetic rsFC as potential marker of FRDA neural reserve.

Psychometric properties of the Friedreich Ataxia Rating Scale

Christian Rummey, Louise A. Corben, Martin B. Delatycki, S.H. Subramony, Khalaf Bushara, Christopher M. Gomez, Joseph Chad Hoyle, Grace Yoon, Bernard Ravina, Katherine D. Mathews, George Wilmot, Theresa Zesiewicz, Susan Perlman, Jennifer M. Farmer, David R. Lynch; Neurol Genet Dec 2019, 5 (6) 371; DOI: 10.1212/NXG.0000000000000371

A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

A new tool to determine the cellular metabolic landscape: nanotechnology to the study of Friedreich’s ataxia

Tommaso Vannocci, Simone Dinarelli, Marco Girasole, Annalisa Pastore & Giovanni Longo; Sci Rep 9, 19282 (2019) doi:10.1038/s41598-019-55799-z

Accordingly, the disease starts appearing when the frataxin levels are below 30% those of healthy controls and are 10–35% the normal levels in FRDA patients. On the other hand, it was found that frataxin overexpression is not a solution as a therapeutic strategy: overexpression seems to be as toxic as its partial depletion. This observation is perfectly coherent with the current hypothesis that frataxin functions as a regulator of the process of conversion of cysteine into alanine through interaction with the desulfurase central to the machine of the iron sulfur cluster biogenesis machine.

Electrophysiological evidence for limited progression of the proprioceptive impairment in Friedreich ataxia

G. Naeije, M. Bourguignon, V. Wens, B. Marty, S. Goldman, R. Hari, V. Jousmäki, M. Pandolfo, X. De Tiège; Clinical Neurophysiology, 2019, Doi: 10.1016/j.clinph.2019.10.021

In any case, our study, using an objective follow-up of upper limb spino-cortical proprioceptive function in FRDA patients, pro- vides additional empirical evidence suggesting limited progressiv- ity of an early established patrhology of dorsal columns and DRG.

Zafgen and Chondrial Therapeutics Announce Definitive Merger Agreement

BOSTON and BALA CYNWYD, Pa., Dec. 18, 2019 (GLOBE NEWSWIRE) -- Zafgen, Inc. (ZFGN) and Chondrial Therapeutics, Inc., today announced they have entered into a definitive merger agreement under which Chondrial will become a wholly-owned subsidiary of Zafgen and the stockholders of Chondrial Therapeutics will become the majority owners of Zafgen’s outstanding common stock upon the close of the merger. The proposed merger will result in a combined publicly traded, clinical-stage biopharmaceutical company operating under a new name, Larimar Therapeutics, Inc.

Creates clinical-stage company focused on the development of novel protein replacement therapies for rare diseases

Chondrial Therapeutics separately announced today that Phase 1 dosing in patients began this month and that CTI-1601 has received Rare Pediatric Disease (RPD) Designation and Fast Track Designation from the U.S. Food and Drug Administration (FDA). Topline results from the Phase 1 clinical program are expected by the end of 2020.

Chondrial Therapeutics Announces Dosing of First Patients in Phase 1 Clinical Program of CTI-1601 for Treatment of Friedreich’s AtaxiaCTI-1601 granted Rare Pediatric Disease Designation and Fast Track Designation by U.S. FDA

BALA CYNWYD, Pa., Dec. 18, 2019 (GLOBE NEWSWIRE) -- Chondrial Therapeutics, a clinical-stage biotechnology company focused on developing treatments for rare diseases, with an initial focus on Friedreich’s ataxia (FA), today announced that the first patients have been dosed in a Phase 1 clinical trial to evaluate the safety and tolerability of single ascending doses of CTI-1601. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin to patients with FA, who have decreased levels of frataxin.

Exicure : Announces First Neurological Development Program in Friedreich's Ataxia and Expands Scientific Advisory Board

12/17/2019, CHICAGO - Exicure, Inc. (NASDAQ: XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) technology, today announced Friedreich's ataxia (FA) as the therapeutic indication for the company's first neurology development program.
Exicure's FA program will be designed and developed with guidance from and in collaboration with FARA.

Cellular Stress-Modulating Drugs Can Potentially Be Identified by in Silico Screening with Connectivity Map (CMap)

Gao Y, Sungwoo Kim, Lee YI, Lee J; International Journal of Molecular Sciences, 09 Nov 2019, 20(22) DOI: 10.3390/ijms20225601

A target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.