In vivo survival and differentiation of Friedreich ataxia iPSC-derived sensory neurons transplanted in the adult dorsal root ganglia

Viventi S, Frausin S, Howden SE, Lim SY, Finol-Urdaneta RK, McArthur JR, Abu-Bonsrah KD, Ng W, Ivanusic J, Thompson L, Dottori M.; Stem Cells Transl Med. 2021 Mar 18. doi: 10.1002/sctm.20-0334. Epub ahead of print. 

 Our data showed survival and differentiation of hESC and FRDA iPSC-derived progenitors in the DRG 2 and 8 weeks post-transplantation, respectively. Donor cells expressed neuronal markers, including sensory and glial markers, demonstrating differentiation to these lineages. These results are novel and a highly significant first step in showing the possibility of using stem cells as a cell replacement therapy to treat DRG neurodegeneration in FRDA as well as other peripheral neuropathies.

Research priorities for rare neurological diseases: a representative view of patient representatives and healthcare professionals from the European Reference Network for Rare Neurological Diseases

Annemarie E. M. Post, Thomas Klockgether, G. Bernhard Landwehrmeyer, Massimo Pandolfo, Astri Arnesen, Carola Reinhard & Holm Graessner. Orphanet J Rare Dis 16, 135 (2021). doi:10.1186/s13023-020-01641-z 

Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and healthcare professionals, asking them to prioritize five research themes for rare neurological diseases on a scale ranging from 1 (most important) to 5 (least important). A follow-up e-mail interview was conducted with patient representatives and professionals to assess potential reasons for differences in opinions between these two groups.

Evaluation of the Effects of Calcitriol's in the Neurological Symptoms of Friedreich's Ataxia Patients (Calcitriol-FA)

ClinicalTrials.gov Identifier: NCT04801303. 

Recruitment Status : Not yet recruiting, First Posted : March 17, 2021, Last Update Posted : March 17, 2021 

 Description of the trial: to assess the effect of Calcitriol 0.25mcg/24h for a year in the neurological function of FA patients. Main objective of the trial: to evaluate the effects of Calcitriol in the neurological symptoms of patients with FA. The second objectives of the trial are: To evaluate the safety and the risk of hypercalcemia with the treatment with low dosis of Calcitriol (0.25mcg of Calcitriol every 24h) in patients with FA. To measure de change in the Frataxin's levels during the treatment with Calcitriol. To evaluate the effects of Calcitriol in the daily life activities and the life quality of the patients with FA. Sample size: The number of participants needed to compleat the trial is 20. 

Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)

Duration: The duration of the trial is one year 

Locations: Spain, Hospital Santa Caterina/Parc Martí i Julià, Salt, Spain, 17190

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice

ural, A., Şimşir, G., Tekgül, Ş., Koçoğlu, C., Akçimen, F., Kartal, E., Şen, N.E., Lahut, S., Ömür, Ö., Saner, N., Gül, T., Bayraktar, E., Palvadeau, R., Tunca, C., Pirkevi Çetinkaya, C., Gündoğdu Eken, A., Şahbaz, I., Kovancılar Koç, M., Öztop Çakmak, Ö., Hanağası, H., Bilgiç, B., Eraksoy, M., Gündüz, A., Apaydın, H., Kızıltan, G., Özekmekçi, S., Siva, A., Altıntaş, A., Kaya Güleç, Z.E., Parman, Y., Oflazer, P., Deymeer, F., Durmuş, H., Şahin, E., Çakar, A., Tüfekçioğlu, Z., Tektürk, P., Çorbalı, M.O., Tireli, H., Akdal, G., Yiş, U., Hız, S., Şengün, İ., Bora, E., Serdaroğlu, G., Erer Özbek, S., Ağan, K., İnce Günal, D., Us, Ö., Kurt, S.G., Aksoy, D., Bora Tokçaer, A., Elmas, M., Gültekin, M., Kumandaş, S., Acer, H., Kaya Özçora, G.D., Yayla, V., Soysal, A., Genç, G., Güllüoğlu, H., Kotan, D., Özözen Ayas, Z., Şahin, H.A., Tan, E., Topçu, M., Topçuoğlu, E.S., Akbostancı, C., Koç, F., Ertan, S., Elibol, B. and Başak, A.N. (2021), Mov Disord. doi.:10.1002/mds.28518 

Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix–Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole‐exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty‐eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data.

Early onset ataxia with Marfanoid features a new varient of Friedreich s ataxia

Khichar S.; IP Indian J Neurosci 2021;7(1):95-96, doi:10.18231/j.ijn.2021.015

A young male with ataxia since early childhood with Marfanoid features, normal intellect and no biochemical abnormality is reported. The syndrome has partial resemblance with previously described syndrome of arachnodactyle, cerebellar ataxia and other features, what has been named as "Bhaskar Syndrome". The documentation of such rare entities is worth for future research.

Design Therapeutics, Inc. (DSGN)

12/3/21. Design Therapeutics is a preclinical-stage biopharmaceutical company pioneering novel small-molecule therapeutic candidates, called gene targeted chimeras (GeneTACs), that are designed to be disease-modifying and target the underlying cause of inherited nucleotide repeat expansion diseases, of which there are more than 40 debilitating degenerative diseases. 

 In preclinical studies for our lead program, we have observed restoration of frataxin (FXN) levels in cells from Friedreich ataxia (FA) patients using our FA GeneTACs. 

 We plan to initiate clinical trials with our lead product candidate in FA patients to evaluate its safety, pharmacokinetics (PK) and effect on FXN levels by the first half of 2022, subject to receiving regulatory clearance to proceed into clinical trials.

Cardiomyopathy of Friedreich's Disease. Modern Methods of Diagnostic

Fomicheva E.I., Myasnikov R.P., Selivyorstov Y.A., Illarioshkin S.N., Dadali E.L., Drapkina O.M. ; Rational Pharmacotherapy in Cardiology. 2021;17(1):105-110. doi:10.20996/1819-6446-2021-01-05 

The basis of the clinical picture of Friedreich's disease is ataxia of a mixed (sensitive and cerebellar) nature. The steady and gradual progression of neurological symptoms significantly affects the quality of life of patients and is most often the leading reason for seeking medical attention. However, the prognosis is primarily due to the involvement of cardiac tissue in the pathological process. The main causes of death in patients with Friedreich's ataxia are severe heart failure and sudden cardiac death due to cardiomyopathy. The overwhelming majority of foreign and domestic publications on Friedreich's ataxia are devoted to the neurological manifestations of this disease, and little attention is paid to this problem in the cardiological scientific and practical society. The purpose of this review is to provide up-to-date information on modern methods of diagnosing myocardial damage at various stages of Friedreich's disease.

Coenzyme Q10 Analogues: Benefits and Challenges for Therapeutics

Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Munuera-Cabeza M, Suárez-Carrillo A, Talaverón-Rey M, Sánchez-Alcázar JA.; Antioxidants. 2021; 10(2):236. doi:10.3390/antiox10020236

  Over the past few years, a wide variety of CoQ10 analogues with improved properties have been developed. These analogues conserve the antioxidant features of CoQ10 but present upgraded characteristics such as water solubility or enhanced mitochondrial accumulation. Moreover, recent studies have proven that some of these analogues might even outperform CoQ10 in the treatment of certain specific diseases. The aim of this review is to provide detailed information about these Coenzyme Q10 analogues, as well as their functionality and medical applications.

This synthetic quinone stands out for its efficacy as a treatment for Friedreich ataxia (FRDA). From 1990 and up to the present, several clinical trials have tested the impact of Idebenone supplementation on patients of FRDA. These studies have proven that the quinone ameliorates patients’ conditions through the improvement of neurological function (reduced general weakness, improvement in fine movement and speech, and decreased difficulty in swallowing) [49] and cardiac hypertrophy (reduction in interventricular septal wall thickness, left ventricular posterior wall thickness, or left ventricular mass index) [50,51]. Idebenone has been widely tested in clinical trials for several years. Its main relevance is in FRDA

Friedreich ataxia in a family from Mali, West Africa

heick Abdel Kader Cissé,Lassana Cissé,Hamidou O Bah,Oumar Samassékou,Assiatou Simaga,Abdoulaye Tamega,Salimata Diarra,Seybou Hassane Diallo,Thomas Coulibaly,Salimata Diallo,Abdoulaye Yalcouye,Alassane Baneye Maiga,Mohamed Kéita,Kenneth Fischbeck,Sekou Fantamady Traore,Cheick Guinto,Guida Landouré; West Africa. Authorea. February 24, 2021. DOI: 10.22541/au.161414432.28217723/v1 

Cissé, CAK, Cissé, L, Ba, HO, et al; from the H3Africa Consortium. Friedreich ataxia in a family from Mali, West Africa/Friedreich ataxia in a Malian family. Clin Case Rep. 2021; 9:e04065.  doi: 10.1002/ccr3.4065

 Friedreich ataxia is the most common inherited ataxia in the world, but yet to be reported in black African. We report the first genetically confirmed case in a West African family. Studying genetic diseases in populations with diverse backgrounds may give new insights into their pathophysiology for future therapeutic targets.

Crosstalk between nucleus and mitochondria in human disease: Mitochondrial iron and calcium homeostasis in Friedreich ataxia

Jordi Tamarit, Elena Britti, Fabien Delaspre, Marta Medina‐Carbonero, Arabela Sanz‐Alcázar, Elisa Cabiscol, Joaquim Ros; IUBMB Life. 2021; 1– 11. https://doi.org/10.1002/iub.2457

 Friedreich Ataxia is a neuro‐cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.