Friedreich cardiomyopathy is a secondary desminopathy

Koeppen, A., Rafique, R., Mazurkiewicz, J., Pelech, S., Sutter, C., Lin, Q., & Qian, J. (2021). Free Neuropathology, 2, 34. doi:10.17879/freeneuropathology-2021-3679 

A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.

Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

Rodden LN, Gilliam KM, Lam C, Lynch DR and Bidichandani SI (2021); Front. Neurosci. 15:752921. doi: 10.3389/fnins.2021.752921 

Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.

Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

CHICAGO & CAMBRIDGE, Mass., December 10, 2021--(BUSINESS WIRE)--Exicure, Inc.® (NASDAQ: XCUR) announced the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline

The results of the investigation are summarized below.

• Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;

• Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;

• The misreported data related solely to efficacy rather than safety of XCUR-FXN;

• The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;

Directors has implemented the following approved plan:

• Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

• Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.

Rad9-mediated checkpoint activation is responsible for elevated expansions of GAA repeats in CST-deficient yeast

Spivakovsky-Gonzalez E, Polleys EJ, Masnovo C, Cebrian J, Molina-Vargas AM, Freudenreich CH, Mirkin SM.; Genetics. 2021 Oct 2;219(2):iyab125. doi: 10.1093/genetics/iyab125. 

 Large-scale expansion of (GAA)n repeats in the first intron of the FXN gene is responsible for the severe neurodegenerative disease, Friedreich's ataxia in humans. We have previously conducted an unbiased genetic screen for GAA repeat instability in a yeast experimental system. The majority of genes that came from this screen encoded the components of DNA replication machinery, strongly implying that replication irregularities are at the heart of GAA repeat expansions. This screen, however, also produced two unexpected hits: members of the CST complex, CDC13 and TEN1 genes, which are required for telomere maintenance. To understand how the CST complex could affect intra-chromosomal GAA repeats, we studied the well-characterized temperature-sensitive cdc13-1 mutation and its effects on GAA repeat instability in yeast. We found that in-line with the screen results, this mutation leads to ∼10-fold increase in the rate of large-scale expansions of the (GAA)100 repeat at semi-permissive temperature. Unexpectedly, the hyper-expansion phenotype of the cdc13-1 mutant largely depends on activation of the G2/M checkpoint, as deletions of individual genes RAD9, MEC1, RAD53, and EXO1 belonging to this pathway rescued the increased GAA expansions. Furthermore, the hyper-expansion phenotype of the cdc13-1 mutant depended on the subunit of DNA polymerase δ, Pol32. We hypothesize, therefore, that increased repeat expansions in the cdc13-1 mutant happen during post-replicative repair of nicks or small gaps within repetitive tracts during the G2 phase of the cell cycle upon activation of the G2/M checkpoint.

Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich’s Ataxia

Bogdanova-Mihaylova, P.; Plapp, H.M.; Chen, H.; Early, A.; Cassidy, L.; Walsh, R.A.; Murphy, S.M.; Tomography 2021, 7, 915-931. doi:10.3390/tomography7040076 

Ocular abnormalities occur frequently in Friedreich’s ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4–40), mean disease duration 19.5 years (range 5–43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5–38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia

Sarah C. Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M. Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Theresa Zesiewicz, Martin B. Delatycki & Louise A. Corben. Cerebellum (2021). doi:10.1007/s12311-021-01348-2 

In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Nuclear Factor Erythroid-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Bianca Seminotti1, Mateus Grings, Paolo Tucci, Guilhian Leipnitz1, Luciano Saso; Front. Cell. Neurosci., 26 November 2021 doi:10.3389/fncel.2021.785057 

We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

Source of medical information and behavioral seeking patterns in patients affected with Friedreich's ataxia and their caregivers: a survey study

Miele G, Lavorgna L, De Mercanti SF, Iudicello M, Abbadessa G, Matta M, Bonavita S, Clerico M.; Neurol Sci. 2021 Nov 28. doi: 10.1007/s10072-021-05738-6. Epub ahead of print. PMID: 34839412. 

For patients and caregivers, the main source of information was the FRDA specialist and the media. The most searched items were "general information"; patients and particularly caregivers desired to get more information on existing and experimental therapies. Adequate information supply is part of good medical care; therefore, a deeper insight of clinicians in information-seeking behavior of FRDA patients and caregivers would provide tailored information and improve therapeutic alliance.

Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia

Emanuele Monda, Michele Lioncino, Marta Rubino, Silvia Passantino, Federica Verrillo, Martina Caiazza, Annapaola Cirillo, Adelaide Fusco, Francesco Di Fraia, Fabio Fimiani, Federica Amodio, Nunzia Borrelli, Alfredo Mauriello, Francesco Natale, Gioacchino Scarano, Francesca Girolami, Silvia Favilli, Giuseppe Limongelli; Heart Failure Clinics, Volume 18, Issue 1, 2022, Pages 31-37, doi:10.1016/j.hfc.2021.07.001. 

Cardiac involvement represents a common disorder in Friedreich ataxia and is responsible for premature death, particularly in early-onset cases. No specific treatments are available for Friedreich ataxia cardiomyopathy. However, gene therapy and stem cells–based therapy might be available as future therapeutic options.

Cellular pathophysiology of Friedreich's ataxia cardiomyopathy

Jarmon G. Lees, Marek Napierala, Alice Pébay, Mirella Dottori, Shiang Y. Lim; International Journal of Cardiology, 2021, doi:10.1016/j.ijcard.2021.11.033. 

At the cellular level, cardiomyocyte hypertrophy, apoptosis and fibrosis contribute to the cardiac pathology. However, the heart is composed of multiple cell types and several clinical studies have reported the involvement of cardiac non-myocytes such as vascular cells, autonomic neurons, and inflammatory cells in the pathogenesis of FRDA cardiomyopathy. In fact, several of the cardiac pathologies associated with FRDA including cardiomyocyte necrosis, fibrosis, and arrhythmia, could be contributed to by a diseased vasculature and autonomic dysfunction. Here, we review available evidence regarding the current understanding of cellular mechanisms for and the involvement of cardiac non-myocytes in the pathogenesis of FRDA cardiomyopathy.