Gentherapie für Ataxien

Zusammenfassung

Ataxien sind progredient verlaufende Krankheiten, die meist Folge einer Degeneration des Kleinhirns sind. Ataxien werden in genetische, sporadisch degenerative und erworbene (sekundäre) Formen unterteilt. Während es bei den erworbene (sekundäre) Ataxien etablierte Therapien gibt, sind genetische und sporadische degenerative Ataxien derzeit nicht medizinisch behandelbar. Für diese Ataxien ist die Entwicklung somatischer Gentherapien ein vielversprechender Weg. Ziele der Gentherapien bei genetischen Ataxien sind die Inaktivierung schädlicher Gene durch Gen-Silencing oder der Ersatz oder die Korrektur eines nicht funktionsfähigen Gens. Eine weitere Option, die auch für sporadisch degenerative Ataxien in Betracht kommt, sind Therapien, bei denen neue oder modifizierte Gene transferiert werden. Bei den häufigeren Ataxien, wie Friedreich-Ataxie, bestimmten spinozerebellären Ataxien und Multisystematrophie werden aktiv Gentherapien entwickelt, und erste Phase I-Studien werden bereits durchgeführt.

Abstract

Ataxias are progressive diseases that are usually the result of cerebellar degeneration. Ataxias are divided into genetic, sporadic degenerative and acquired (secondary) forms. While there are established therapies for acquired (secondary) ataxias, genetic and sporadic degenerative ataxias are currently not medically treatable. For these ataxias, the development of somatic gene therapies is a promising avenue. The goals of gene therapies for genetic ataxias are to inactivate deleterious genes by gene silencing or to replace or correct a non-functional gene. Another option, which may also be considered for sporadic degenerative ataxias, are therapies that involve transferring new or modified genes. Gene therapies are being actively developed for the more common ataxias, such as Friedreich’s ataxia, certain spinocerebellar ataxias, and multiple system atrphy, and initial phase I trials are underway.

Schlüsselwörter

Antisense-Oligonukleotide - Ataxie - Gen-Silencing - Multisystematrophie - Repeat-Mutation

Key words

Antisense oligonucleotides - Ataxia - Gene silencing - Multiple system atrophy - Repeat mutation

Publication History

Received: 22 September 2022

Accepted: 10 January 2023

Article published online:
20 February 2023

• Literatur

• 1 Synofzik M, Puccio H, Mochel F. et al. Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies. Neuron 2019; 101: 560-583 DOI: 10.1016/j.neuron.2019.01.049.
• 2 Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat. Rev. Dis. Primers 2019; 5: 24
• 3 Klockgether T. Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol 2010; 9: 94-104
• 4 Perlman S, Boltshauser E. Drug treatment. Handb Clin Neurol. 2018; 155: 371-377 DOI: 10.1016/B978-0-444-64189-2.00024-X.
• 5 Benussi A, Pascual-Leone A, Borroni B. Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review. Int J Mol Sci 2020; 21 DOI: 10.3390/ijms21061948.
• 6 Benussi A, Dell’Era V, Cantoni V. et al. Cerebello-spinal tDCS in ataxia: A randomized, double-blind, sham-controlled, crossover trial. Neurology 2018; 91: e1090-e1101
• 7 Maas RPPWM, Teerenstra S, Toni I. et al. Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial. Neurotherapeutics 2022; 19: 1259-1272 DOI: 10.1007/s13311-022-01231-w.
• 8 Synofzik M, Ilg W. Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames. Biomed Res Int 2014; 2014: 583507
• 9 Vázquez-Mojena Y, León-Arcia K, González-Zaldivar Y. et al. Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives. Mov Disord 2021; 36: 2731-2744 DOI: 10.1002/mds.28819.
• 10 Carranza D, Torres-Rusillo S, Ceballos-Pérez G. et al. Reconstitution of the Ataxia-Telangiectasia Cellular Phenotype With Lentiviral Vectors. Front Immunol 2018; 9: 2703 DOI: 10.3389/fimmu.2018.02703.
• 11 Du L, Pollard JM, Gatti RA. Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides. Proc Natl Acad Sci U. S. A 2007; 104: 6007-6012 DOI: 10.1073/pnas.0608616104.
• 12 Anthony K. RNA-based therapeutics for neurological diseases. RNA Biol 2022; 19: 176-190 DOI: 10.1080/15476286.2021.2021650.
• 13 Pandolfo M, Pastore A. The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J Neurol 2009; 256: 9-17
• 14 Meseck EK, Guibinga G, Wang S. et al. Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques. Toxicol Pathol 2022; 50: 415-431 DOI: 10.1177/01926233221101309.
• 15 Nabhan JF, Wood KM, Rao VP. et al. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia. Sci Rep 2016; 6: 20019 DOI: 10.1038/srep20019.
• 16 Perdomini M, Belbellaa B, Monassier L. et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. NATURE MEDICINE 2014; 20: 542-547 DOI: 10.1038/nm.3510.
• 17 Huichalaf C, Perfitt TL, Kuperman A. et al. In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency. Mol Ther Methods Clin Dev 2022; 24: 367-378 DOI: 10.1016/j.omtm.2022.02.002.
• 18 Piguet F, de Montigny C, Vaucamps N. et al. Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia. Mol Ther 2018; 26: 1940-1952 DOI: 10.1016/j.ymthe.2018.05.006.
• 19 Kordasiewicz HB, Stanek LM, Wancewicz EV. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 2012; 74: 1031-1044 DOI: 10.1016/j.neuron.2012.05.009.
• 20 Keiser MS, Kordower JH, Gonzalez-Alegre P. et al. Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. Brain 2015; 138: 3555-3566 DOI: 10.1093/brain/awv292.
• 21 Scoles DR, Meera P, Schneider MD. et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 2017; 544: 362-366
• 22 McLoughlin HS, Moore LR, Chopra R. et al. Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann. Neurol. 2018
• 23 O’Callaghan B, Hofstra B, Handler HP. et al. Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment. Mol. Ther. Nucleic Acids 2020; 21: 1006-1016 DOI: 10.1016/j.omtn.2020.07.030.
• 24 Niu C, Prakash TP, Kim A. et al. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med 2018; 10 DOI: 10.1126/scitranslmed.aap8677.
• 25 Kourkouta E, Weij R, González-Barriga A. et al. Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide. Mol Ther Nucleic Acids 2019; 17: 601-614 DOI: 10.1016/j.omtn.2019.07.004.
• 26 Hauser S, Helm J, Kraft M. et al. Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons. Mol Ther Nucleic Acids 2022; 27: 99-108 DOI: 10.1016/j.omtn.2021.11.015.
• 27 Keiser MS, Monteys AM, Corbau R. et al. RNAi prevents and reverses phenotypes induced by mutant human ataxin-1. Ann Neurol 2016; 80: 754-765 DOI: 10.1002/ana.24789.
• 28 Keiser MS, Boudreau RL, Davidson BL. Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy. Mol Ther 2014; 22: 588-595 DOI: 10.1038/mt.2013.279.
• 29 Carrell EM, Keiser MS, Robbins AB. et al. Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice. Mol Ther Methods Clin Dev 2022; 25: 333-343 DOI: 10.1016/j.omtm.2022.04.004.
• 30 Keiser MS, Ranum PT, Yrigollen CM. et al. Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain. NATURE MEDICINE 2021; 27: 1982-1989 DOI: 10.1038/s41591-021-01522-3.
• 31 Nobre RJ, Lobo DD, Henriques C. et al. miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3. Nucleic Acid Ther 2022; 32: 194-205 DOI: 10.1089/nat.2021.0020.
• 32 Alves S, Nascimento-Ferreira I, Auregan G. et al. Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 2008; 3: e3341 DOI: 10.1371/journal.pone.0003341.
• 33 Conceição M, Mendonça L, Nóbrega C. et al. Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype. Biomaterials 2016; 82: 124-137 DOI: 10.1016/j.biomaterials.2015.12.021.
• 34 Derbis M, Kul E, Niewiadomska D. et al. Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats. Nat Commun 2021; 12: 1265 DOI: 10.1038/s41467-021-21021-w.
• 35 Wenning GK, Stefanova N, Jellinger KA. et al. Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 2008; 64: 239-246