Abstract
Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders, including the genetic group of nucleotide repeat disorders. The mechanisms leading to the clinical deficits have been greatly clarified with the advent of genetic studies, novel neuroimaging tools, and the development of cellular/animal models recapitulating neuronal defects in humans. Targeting the DNA and the RNA represents a highly promising approach in so-called degenerative ataxias, previously considered as untreatable disorders. Disease-modifying treatments of CAs have become a reality and will likely be administered on a regular basis in selected CAs during this decade.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S et al (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315:1709–1712
Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P et al (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544(7650):367–371
Bettencourt C, Hensman-Moss D, Flower M, Wiethoff S, Brice A, Goizet C et al (2016) DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann Neurol 79(6):983–990
Chew WL (2018) Immunity to CRISPR Cas9 and Cas12a therapeutics. Wiley Interdiscip Rev Syst Biol Med 10:e1408
Ciosi M, Maxwell A, Cumming SA, Hensman Moss DJ, Alshammari AM, Flower MD et al (2019) A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48:568–580
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823
Deelchand DK, Joers JM, Ravishankar A et al (2019) Sensitivity of volumetric magnetic resonance imaging and magnetic resonance spectroscopy to progression of spinocerebellar ataxia type 1. Mov Disord Clin Pract 6(7):549–558
Deshmukh AL, Porro A, Mohiuddin M, Lanni S, Panigrahi GB, Caron MC, Masson JY, Sartori AA, Pearson CE (2021) FAN1, a DNA repair nuclease, as a modifier of repeat expansion disorders. J Huntingtons Dis 10:95–122
Florea AM, Busselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel) 3:1351–1371
Gottesfeld JM (2019) Molecular mechanisms and therapeutics for the GAA·TTC expansion disease Friedreich ataxia. Neurotherapeutics 16:1032–1049
Hirakawa MP, Krishnakumar R, Timlin JA, Carney JP, Butler KS (2020) Gene editing and CRISPR in the clinic: current and future perspective. Biosci Rep 40:BSR20200127
**ek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821
Klockgether T, Mariotti C, Paulson HL (2019) Spinocerebellar ataxia. Nat Rev Dis Primers 5(1):24
Kuo SH (2019) Ataxia. Continuum (Minneap Minn) 25(4):1036–1054
Lin XP, Feng L, **e CG et al (2014) Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease. Int J Dev Neurosci 38:17–22
Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE et al (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826
McLoughlin HS, Moore LR, Chopra R, Komlo R, McKenzie M, Blumenstein KG, Zhao H, Kordasiewicz HB, Shakkottai VG, Paulson HL (2018) Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84(1):64–77
Mergener R, Furtado GV, de Mattos EP, Leotti VB, Jardim LB, Saraiva-Pereira ML (2020) Variation in DNA repair system gene as an additional modifier of age at onset in spinocerebellar ataxia type 3/Machado-Joseph disease. Neuromolecular Med 22(1):133–138
Mojica FJ, Diez-Villasenor C, Soria E, Juez G (2000) Biological significance of a family of regularly spaced repeats in the genomes of Archaea, Bacteria and mitochondria. Mol Microbiol 36:244–246
Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, Gattis D, Hung G, Kordasiewicz HB, Paulson HL, McLoughlin HS (2017) Evaluation of antisense oligonucleotides targeting ATXN3 in SCA3 mouse models. Mol Ther Nucleic Acids 7:200–210
Perlman S, Boltshauser E (2018) Drug treatment. Handb Clin Neurol 155:371–377
Ramachandran PS, Boudreau RL, Schaefer KA et al (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22(9):1635–1642
Scoles DR, Meera P, Schneider MD, Paul S, Dansithong W, Figueroa KP, Hung G, Rigo F, Bennett CF, Otis TS, Pulst SM (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544(7650):362–366
Shen X, Kilikevicius A, O’Reilly D et al (2018) Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion. Bioorg Med Chem Lett 28(17):2850–2855
Shen K, Gamerdinger M, Chan R et al (2019) Dual Role of Ribosome-Binding Domain of NAC as a potent suppressor of protein aggregation and aging-related proteinopathies. Mol Cell 74:729–741
Shirai S, Yabe I, Takahashi-Iwata I et al (2019) The responsiveness of triaxial accelerometer measurement of gait ataxia is higher than that of the scale for the assessment and rating of ataxia in the early stages of spinocerebellar degeneration. Cerebellum 18(4):721–730
Sternberg SH, Doudna JA (2015) Expanding the biologist’s toolkit with CRISPR-Cas9. Mol Cell 58:568–574
Sullivan R, Yau WY, O’Connor E, Houlden H (2019) Spinocerebellar ataxia: an update. J Neurol 266:533–544
Synofzik M, Puccio H, Mochel F, Schöls L (2019) Autosomal recessive cerebellar ataxias: paving the way toward targeted molecular therapies. Neuron 101(4):560–583
Toonen LJA, Rigo F, van Attikum H, van Roon-Mom WMC (2017) Antisense oligonucleotide-mediated removal of the polyglutamine repeat in spinocerebellar ataxia type 3 mice. Mol Ther Nucleic Acids 8:232–242
Wiedenheft B, Sternberg SH, Doudna JA (2012) RNA-guided genetic silencing systems in bacteria and archaea. Nature 482:331–338
Zain R, Smith CIE (2019) Targeted oligonucleotides for treating neurodegenerative tandem repeat diseases. Neurotherapeutics 16(2):248–262
Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH (2015) Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther Nucleic Acids 4:e264
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Ethics declarations
The authors declare no conflict of interest.
Funding
This work was conducted without any funding from public or private sources.
Ethical Committee Request
Not applicable.
Consent to Participate
Not applicable.
Data Availability
The chapter is not associated with raw data.
Code Availability
There is no software application or custom code used in this paper.
Authors’ Contribution
Chapter preparation: JG. Editing: MM. All authors have read and agreed to the publication.
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Gandini, J., Manto, M. (2023). Editing the Genome. In: Gruol, D.L., Koibuchi, N., Manto, M., Molinari, M., Schmahmann, J.D., Shen, Y. (eds) Essentials of Cerebellum and Cerebellar Disorders. Springer, Cham. https://doi.org/10.1007/978-3-031-15070-8_108
Download citation
DOI: https://doi.org/10.1007/978-3-031-15070-8_108
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-15069-2
Online ISBN: 978-3-031-15070-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)