The inherited cerebellar ataxias: an update

Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M.; J Neurol. 2022 Sep 24. doi: 10.1007/s00415-022-11383-6. 

We describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

Diagnostic Delay and Clinical Features in Friedreich’s Ataxia

Mehmet Fatih Yetkin, Murat Gültekin, Merve Akcakoyunlu, Recep Baydemir, Ayse Çağlar Sarılar, Mehmet Canpolat, Hüseyin Per; Turk Noroloji Dergisi, cilt.28, sa.2, ss.97-101, 2022 (Hakemli Dergi). DOI:10.4274/tnd.2022.26780

Conclusion: This study is the first study to evaluate the diagnosis delay in patients with FRDA in our country. Although FRDA was the most common hereditary ataxia, in our study, it was shown that there was a significant delay in diagnosis in patients with FRDA. There is a need for studies that will raise awareness of public and health professionals about FRDA.

FRIEDREICH'S ATAXIA AND ITS CARDIOVASCULAR MANIFESTATIONS

Bryam Esteban Coello Garcia, Karina Noemi Contreras Garcia, Priscila Jazmin Sarango Lapo, Tatiana Carolina Espinoza Coyago, Johanna Belen Illescas Aguilera, Bonny Maria Montalvan Nivicela, Karen Sofia Suscal Pelaez; EPRA International Journal of Multidisciplinary Research (IJMR) -Volume: 8, Issue: 9, September 2022, DOI:10.36713/epra11261 

 The aim of this bibliographic review is to inform the scientific community of the presence of systemic manifestations, especially cardiovascular, in Friedreich's Ataxia; since this disease is not only characterized by the presence of neurological alterations, but also of affections to different apparatuses and systems of the human body, such as the heart, due to the cellular alteration that Friedreich's Ataxia causes.

Gene Expression Quantification to Assess Frataxin Replacement Therapies in Friedreich’s Ataxia

M. Baile, D. Schecter, A. Miller, T. Galas, N. Scherer, R. Chen, N. Ruiz, D. Bettoun.; Mov Disord. 2022; 37 (suppl 1). Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

 Quantitation of expression levels of a small number of genes in buccal cells can be used to discriminate between healthy individuals and patients with FRDA. Treatment with CTI-1601 is effective in restoring the expression levels of 6 of those genes to levels similar to those observed in healthy individuals.

Tissue Frataxin Increases After Administration of CTI-1601, a Frataxin Replacement Therapy in Development for the Treatment of Friedreich’s Ataxia

D. Bettoun, T. Galas, D. Schecter, N. Ruiz, R. Clayton, J. Farmer.; Mov Disord. 2022; 37 (suppl 1).Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

In this first clinical study of CTI-1601, a therapy intended to increase FXN in patients with FRDA, increases in FXN levels were seen in multiple tissues. These observed increases in FXN after 7 days of QD dosing of 50 or 100 mg CTI-160 are potentially clinically relevant since 2- to 3-fold increases in FXN in patients with FRDA may achieve FXN levels observed in asymptomatic heterozygous carriers [1, 2]. CTI-1601 was generally well-tolerated. These data support the continued study of CTI-1601 as a treatment for patients with FRDA.

Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes

Cotticelli MG, Xia S, Truitt R, Doliba NM, Rozo AV, Tobias JW, Lee T, Chen J, Napierala JS, Napierala M, Yang W, Wilson RB.; Dis Model Mech. 2022 Sep 15:dmm.049497. doi: 10.1242/dmm.049497 

We confirmed that in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.

The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

Ning Guo, Ji-Bin Liu, Wen Li, Yu-Shui Ma, Da Fu; Journal of Advanced Research, Volume 40, 2022, Pages 135-152, doi:10.1016/j.jare.2021.11.018. 

CRISPR/Cas9 also provides a possible therapeutic strategy for Friedreich's ataxia (FRDA). For example, removing the GAA expansions of the frataxin gene (FXN) in vitro and in vivo alleviates related symptoms dramatically but with some unexpected side effects like p53-mediated cell proliferation delay.

A Study to Assess the Safety and Efficacy of Vatiquinone in Participants With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05515536

The primary objective of this study is to assess the long-term safety of vatiquinone in participants with Friedreich ataxia (FA) previously exposed to vatiquinone in Study PTC743-NEU-003-FA (NCT04577352) or Study PTC743-NEU-005-FA

Phase 3 

Study Type : Interventional (Clinical Trial) 

Estimated Enrollment : 140 participants 

Allocation: N/A 

Intervention Model: Single Group Assignment 

Masking: None (Open Label) 

Primary Purpose: Treatment 

Official Title: Long-Term Open-Label Study to Assess the Safety and Efficacy of Vatiquinone in Patients With Friedreich Ataxia 

Estimated Study Start Date : November 1, 2022 

Estimated Primary Completion Date : December 31, 2027 

Estimated Study Completion Date : December 31, 2027

Consideration of oral health in rare disease expertise centres: a retrospective study on 39 rare diseases using text mining extraction method

Friedlander, L., Vincent, M., Berdal, A. et al.; Orphanet J Rare Dis 17, 317 (2022). doi:10.1186/s13023-022-02467-7 

Five networks we studied fill in the patient database while their phenotypes predict that dental and oral phenotypes may raise difficulties. The analysis of the collected data suggests a lack of connection with oral professionals during early childhood and adult transition. These networks are BRAIN-TEAM with Friedreich ataxia (Rare diseases with motor or cognitive expression of the central nervous system)......

Resveratrol from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Khattar, Shivani, Sauban Ahmed Khan, Syed Amir Azam Zaidi, Mahdi Darvishikolour, Uzma Farooq, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kurunian, Mohammed Zaafar Khan, Athar Shamim, Mohd Masih Uzzaman Khan, Zeenat Iqbal, and Mohd. Aamir Mirza. 2022.; Pharmaceuticals 15, no. 8: 957. doi:10.3390/ph15080957

In Australia, RVT as an option for the treatment of Friedreich ataxia was assessed ( NCT01339884, A Study of Resveratrol as Treatment for Friedreich Ataxia, Phase 1, Phase 2)