Friedreich ataxia: clinical features and new developments

Medina Keita, Kellie McIntyre, Layne N Rodden, Kim Schadt, and David R Lynch; Neurodegenerative Disease Management 0 0:0. Published Online:29 Jun 2022 ; doi:10.2217/nmt-2022-0011 

 Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000–100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.

What role can decentralized trial designs play to improve rare disease studies?

Moore, J., Goodson, N., Wicks, P. et al.; Orphanet J Rare Dis 17, 240 (2022). doi:10.1186/s13023-022-02388-5

DCT approaches have been shown to be more resilient to changes in enrolment and attrition during COVID-19 than traditional designs and offer benefits in terms of patient burden, convenience, inclusion, and data quality. Digital tools such as wearable devices and electronic clinical outcome assessments may also provide more convenient and environmentally valid measures of how a condition affects the life of an individual in their regular environment (e.g. mobility around the home versus a hospital corridor). Digital solutions have greater ability to support language localization, accessibility, and may lead to increase access to global rare disease trials. In parallel, challenges exist, such as the technical support, the digital divide, ensuring high quality data, and delivering safe trials.

Discovery of Therapeutics Targeting Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic Review

Lew, S.Y.; Phang, M.W.L.; Chong, P.S.; Roy, J.; Poon, C.H.; Yu, W.S.; Lim, L.W.; Wong, K.H.; Pharmaceuticals 2022, 15, 764. doi:10.3390/ph15060764 

We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia

Sivakumar A and Cherqui S (2022); Front. Genome Ed. 4:903139. doi: 10.3389/fgeed.2022.903139

Recent research on in vivo and ex vivo gene therapy methods in FRDA animal and cell models showcase its promise as a one-time therapy for FRDA. In this review, we provide an overview on the current and emerging prospects of gene therapy for FRDA, with specific focus on advantages of CRISPR/Cas9-mediated gene editing of FXN as a viable option to restore endogenous frataxin expression. We also assess the potential of ex vivo gene editing in hematopoietic stem and progenitor cells as a potential autologous transplantation therapeutic option and discuss its advantages in tackling FRDA-specific safety aspects for clinical translation.

Guía práctica de evaluación de pacientes con ataxias y paraparesias espásticas hereditarias en consulta

F.J. Arpa Gutiérrez, M.J. Abenza Abildúa, I. Rouco Axpeb, A.D. Adarmes Gómez, C. Serrano Munuera; Neurología, doi:10.1016/j.nrl.2022.02.004

Esta guía pretende facilitar la asistencia clínica diaria por parte del neurólogo y unificar los criterios médicos y la metodología de evaluación de la discapacidad de los pacientes con AH y paraparesias espásticas hereditarias.

Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich’s ataxia

Yanjie Li, Jixue Li, Jun Wang, Siyuan Zhang, Keith Giles, Thazha P Prakash, Frank Rigo, Jill S Napierala, Marek Napieral; Human Molecular Genetics, 2022;, ddac134, doi:10.1093/hmg/ddac134 

The level the FXN-ett RNA directly correlates with the length of the longer of the two expanded GAA tracts. Targeting GAAs with antisense oligonucleotides or excision of the repeats eliminates the transcription impediment, diminishes expression of the aberrant FXN-ett, while increasing levels of FXN mRNA and frataxin. Non-productive transcription may represent a common phenomenon and attractive therapeutic target in diseases caused by repeat-mediated transcription aberrations.

Metabolomics analysis reveals dysregulation in one carbon metabolism in Friedreich Ataxia

Thomas M. O'Connell, David L. Logsdon, R. Mark Payne; Molecular Genetics and Metabolism, 2022, ISSN 1096-7192, doi:10.1016/j.ymgme.2022.06.002. 

These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.

W131 Detection of compound heterozygotes for GAA expansion & a frataxin gene (FXN) point mutation in patients with friedreich’s ataxia

A. Pagdhune, A. Dalal, M. M; Clinica Chimica Acta, Volume 530, Supplement 1, 2022, Page S341, ISSN 0009-8981, doi:10.1016/j.cca.2022.04.886.

Frataxin Deficit Leads to Reduced Dynamics of Growth Cones in Dorsal Root Ganglia Neurons of Friedreich’s Ataxia YG8sR Model: A Multilinear Algebra Approach

Muñoz-Lasso DC, Mollá B, Sáenz-Gamboa JJ, Insuasty E, de la Iglesia-Vaya M, Pook MA, Pallardó FV, Palau F and Gonzalez-Cabo P (2022). Front. Mol. Neurosci. 15:912780. doi: 10.3389/fnmol.2022.912780

In summary, we have evidenced an adverse effect of the deficit of frataxin in the formation and, most importantly, the growth cones’ function in adult DRG neurons by applying both classical and novel computer-assisted analysis. As a result, we propose that frataxin deficient DRG neurons might lose the intrinsic capacity to grow and regenerate axons properly due to the dysfunctional GCs they build.

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Hanaford, A.R., Cho, YJ. & Nakai, H.; Orphanet J Rare Dis 17, 217 (2022). doi:10.1186/s13023-022-02324-7 

This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Friedreich ataxia, Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.

Neuroinflammation in Friedreich’s Ataxia

Apolloni, S.; Milani, M.; D’Ambrosi, N.; Int. J. Mol. Sci. 2022, 23, 6297. doi:10.3390/ijms23116297

In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.

A clinical and epidemiological prevalence study on Friedreich's Ataxia in Latium, Italy

Romano S, Bacigalupo I, Marcotulli C, Cioffi E, Bertini ES, Vasco G, Perna A, Petrucci A, Massa R, Frezza E, Romano C, Salvetti M, Ristori G, Silvestri G, Vanacore N, Casali C.; Neuroepidemiology. 2022 May. DOI: 10.1159/000525159. PMID: 35636410.

We estimated the crude and standardized prevalence of FRDA in Latium. A clinical classification (EOFA, LOFA, VLOFA) gave significant correlations. This epidemiological estimate allows to monitor a disease prevalence over time in cohort studies, and/or for developing disease registry.

Metal Ion Binding in Wild-Type and Mutated Frataxin: A Stability Study

Morante, S.; Botticelli, S.; Chiaraluce, R.; Consalvi, V.; La Penna, G.; Novak, L.; et al. (2022); Frontiers. Collection. doi:10.3389/fmolb.2022.878017

We can explain the surprising feature emerging from a detailed analysis of the XANES region of the spectrum, showing that the longer 81-210 frataxin fragment has a smaller propensity for Co2+ binding than the shorter 90-210 one. This fact is explained by the peculiar role of the N-terminal disordered tail in modulating the protein ability to interact with the metal.