Subscribe to RSS
Download PDF
DOI: 10.1055/a-2002-5176
Einführung in die Gentherapie
Introduction to Gene Therapy
Zusammenfassung
Nach vielen Jahren der Entwicklung und zahlreichen Rückschlägen hat die Gentherapie, also die direkte therapeutische Modifikation der Gene auf DNA- oder RNA-Ebene, erste unbestreitbare Erfolge. Dabei werden sowohl „ex vivo“ Verfahren, also die genetische Manipulation von zuvor entnommenen Körperzellen, als auch „in vivo“ Methoden erfolgreich eingesetzt. Neben dem Ersatz fehlender oder schadhafter Gene können auch die Korrektur der DNA-Sequenz durch die CRISPR-Cas9-„Genschere“ und die sequenzspezifische Beeinflussung der Genexpression auf RNA-Ebene als gentherapeutische Methoden im weiteren Sinne bezeichnet werden.
Abstract
After many years of research and numerous setbacks, there are now undeniable success stories of gene therapies, namely the direct modification of genetic information on the DNA or RNA level. Both “ex vivo” strategies, i. e. the genetic manipulation of patient cells in a dish, as well as “in vivo” approaches are being used successfully. In addition to the supplementation of defective genes, the use of the CRISPR-Cas9 system to alter nuclear DNA sequences and the sequence-specific interference with the transcriptional process on the RNA level can be designated as gene therapies in a broad sense.
Publication History
Received: 14 September 2022
Accepted: 12 December 2022
Article published online:
20 February 2023
© 2023. Thieme. All rights reserved.
Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart,
Germany
-
Literatur
- 1 Finkel RS. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377: 1723-1732
- 2 Mendell JR. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017; 377: 1713-1722
- 3 Weiss C, Ziegler A, Becker LL, Johannsen J, Brennenstuhl H, Schreiber G. et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc Health 2022; 6: 17-27
- 4 Jensen TL, Gotzsche CR, Woldbye DPD. Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord. Frontiers in molecular neuroscience 2021; 14: 695937
- 5 Skokowa J. Circumventing Mutation to Nix Neutropenia. N Engl J Med 2021; 384: 1956-1958
- 6 Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML. et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med 2021; 385: 493-502
- 7 Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK. et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med 2018; 379: 22-31
- 8 Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV. et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018; 379: 11-12
- 9 Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin Lowering Strategies for Disease Modification in Huntington's Disease. Neuron 2019; 102: 899
- 10 Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA. et al. Targeting Huntingtin Expression in Patients with Huntington's Disease. N Engl J Med 2019; 380: 2307-2316
- 11 Kwon D. Failure of genetic therapies for Huntington's devastates community. Nature 2021; 593: 180
- 12 Kingwell K. Double setback for ASO trials in Huntington disease. Nat Rev Drug Discov 2021; 20: 412-413
- 13 Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 2006; 116: 2290-2296
- 14 Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013; 12: 435-442
- 15 Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC. et al. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med 2020; 383: 109-119
- 16 Mullard A. ALS antisense drug falters in phase III. Nat Rev Drug Discov 2021; 20: 883-885
- 17 Synofzik M, van Roon-Mom WMC, Marckmann G, van Duyvenvoorde HA, Graessner H, Schule R. et al. Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives. Nucleic Acid Ther 2022; 32: 83-94
- 18 Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A. et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med 2019; 381: 1644-1652