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DOI: 10.1055/a-2042-2338
Gentherapie der Huntington-Krankheit
Gene Therapy for Huntington Disease
Zusammenfassung
Deutsch: Als häufige genetisch bedingte neurodegenerative Erkrankung ist die Huntington-Krankheit eine Modellerkrankung – auch für die Gentherapie. Unter den unterschiedlichen Möglichkeiten ist die Entwicklung von Antisense-Oligonukleotiden am weitesten fortgeschritten. Als weitere Optionen auf Ebene der RNA stehen Mikro-RNAs und Modulatoren der RNA-Prozessierung (Spleißen) zur Verfügung, auf DNA-Ebene Zink-Finger-Proteine. Mehrere Produkte befinden sich in der klinischen Prüfung. Diese unterscheiden sich in Applikationsform und systemischer Verfügbarkeit, aber auch in der genauen Wirkung. Ein wichtiger Unterschied könnte darin liegen, ob alle Formen des Huntingtin-Proteins gleichermaßen von der Therapie angesprochen werden, oder ob sich die Therapie präferentiell gegen besonders toxische Formen wie das Exon1-Protein richtet. Die Ergebnisse der kürzlich abgebrochenen GENERATION HD1 Studie waren etwas ernüchternd, am ehesten aufgrund der nebenwirkungsbedingten Liquorzirkulationsstörung. Sie sind daher nur ein Schritt in der Entwicklung zu einer wirksamen Gentherapie gegen die Huntington-Krankheit.
Abstract
Englisch: Being one of the most common genetic neurodegenerative disease, Huntington’s disease has been a model disease – also for gene therapy. Among the various options, the development of antisense oligonucleotides is the most advanced. Further options at the RNA level include micro-RNAs and modulators of RNA processing (splicing), at the DNA level zinc finger proteins. Several products are in clinical trials. These differ in their mode of application and in the extent of systemic availability. Another important difference between therapeutic strategies could be whether all forms of the huntingtin protein are targeted in the same extent, or whether a therapy preferentially targets particular toxic forms such as the exon1 protein. The results of the recently terminated GENERATION HD1 trial were somewhat sobering, most likely due to the side effect-related hydrocephalus. Therefore they represent just one step towards the development of an effective gene therapy against Huntington’s disease.
Publication History
Received: 01 September 2022
Accepted: 16 February 2023
Article published online:
11 April 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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Literatur
- 1 Saudou F, Humbert S. The Biology of Huntingtin. Neuron 2016; 89: 910-926 DOI: 10.1016/j.neuron.2016.02.003.
- 2 Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10: 83-98 DOI: 10.1016/S1474-4422(10)70245-3.
- 3 Frank W, Lindenberg KS, Mühlbäck A. et al. Krankheitsmodifizierende Therapieansätze bei der Huntington-Krankheit: Blicke zurück und Blicke voraus. Nervenarzt 2022; 93: 179-190 DOI: 10.1007/s00115-021-01224-8.
- 4 Keryer G, Pineda JR, Liot G. et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest 2011; 121: 4372-4382 DOI: 10.1172/JCI57552.
- 5 Stilling S, Kalliakoudas T, Benninghoven-Frey H. et al. PIP2 determines length and stability of primary cilia by balancing membrane turnovers. Commun Biol 2022; 5: 93 DOI: 10.1038/s42003-022-03028-1.
- 6 Cubo E, Martinez-Horta S-I, Santalo FS. et al. Clinical manifestations of homozygote allele carriers in Huntington disease. Neurology 2019; 10.1212/WNL.0000000000007147 DOI: 10.1212/WNL.0000000000007147.
- 7 Hoffner G, Soues S, Djian P. Aggregation of Expanded Huntingtin in the Brains of Patients with Huntington Disease. Prion 2007; 1: 26-31 DOI: 10.4161/pri.1.1.4056.
- 8 Neueder A, Landles C, Ghosh R. et al. The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients. Sci Rep 2017; 7: 1307 DOI: 10.1038/s41598-017-01510-z.
- 9 Yang S, Yang H, Huang L. et al. Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice. Proc Natl Acad Sci 2020; 117: 4411-4417 DOI: 10.1073/pnas.1919197117.
- 10 Mouro Pinto R, Arning L, Giordano JV. et al. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1. Hum Mol Genet 2020; 29: 2551-2567 DOI: 10.1093/hmg/ddaa139.
- 11 Scahill RI, Zeun P, Osborne-Crowley K. et al. Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol 2020; 19: 502-512 DOI: 10.1016/S1474-4422(20)30143-5.
- 12 Falkenburger B. [Huntington’s disease and Sydenham’s chorea]. Fortschr Neurol Psychiatr 2020; 88: 403-415 DOI: 10.1055/a-1124-0060.
- 13 Beste C, Stock A-K, Ness V. et al. A novel cognitive-neurophysiological state biomarker in premanifest Huntington’s disease validated on longitudinal data. Sci Rep 2013; 3: 1797 DOI: 10.1038/srep01797.
- 14 Epping EA, Kim J-I, Craufurd D. et al. Longitudinal Psychiatric Symptoms in Prodromal Huntington’s Disease: A Decade of Data. Am J Psychiatry 2016; 173: 184-192 DOI: 10.1176/appi.ajp.2015.14121551.
- 15 Paulsen JS, Langbehn DR, Stout JC. et al. Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 2008; 79: 874-880 DOI: 10.1136/jnnp.2007.128728.
- 16 Tabrizi SJ, Langbehn DR, Leavitt BR. et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8: 791-801 DOI: 10.1016/S1474-4422(09)70170-X.
- 17 Sánchez-Pernaute R, Künig G, del Barrio Alba A. et al. Bradykinesia in early Huntington’s disease. Neurology 2000; 54: 119-125 DOI: 10.1212/wnl.54.1.119.
- 18 Bachoud-Lévi A-C, Ferreira J, Massart R. et al. International Guidelines for the Treatment of Huntington’s Disease. Front Neurol 2019; 10: 710 DOI: 10.3389/fneur.2019.00710.
- 19 Achenbach J, von Hein SM, Saft C. Functional and cognitive capacity differ in dystonic motor subtypes when compared to choreatic and hypokinetic-rigid motor subtypes in Huntington’s disease. Brain Behav 2020; 10: e01704 DOI: 10.1002/brb3.1704.
- 20 Saft C. et al. S2k-Leitlinie Chorea/Morbus Huntington. 2017. In: Deutsche Gesellschaft für Neurologie, Hrsg. Leitlinien für Diagnostik und Therapie in der Neurologie. Im Internet: https://register.awmf.org/assets/guidelines/030-028l_S2k_Chorea_Morbus_Huntington_2017-12_1.pdf; Stand 01.11.2022
- 21 Achenbach J, Thiels C, Lücke T. et al. Clinical Manifestation of Juvenile and Pediatric HD Patients: A Retrospective Case Series. Brain Sci 2020; 10: E340 DOI: 10.3390/brainsci10060340.
- 22 Ferguson MW, Kennedy CJ, Palpagama TH. et al. Current and Possible Future Therapeutic Options for Huntington’s Disease. J Cent Nerv Syst Dis 2022; 14: 117957352210925 DOI: 10.1177/11795735221092517.
- 23 Tabrizi SJ, Leavitt BR, Landwehrmeyer GB. et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N Engl J Med 2019; 380: 2307-2316 DOI: 10.1056/NEJMoa1900907.
- 24 Online presentation on the Roche and Genentech tominersen programme. Im Internet: http://www.ehdn.org/recording-meeting-jan-2022/; Stand 27.08.2022
- 25 A Ph1b/2a study of WVE-003, an investigational allele-selective, mHTT–lowering oligonucleotide for the treatment of early manifest Huntington’s disease, and review of PRECISION-HD results. Im Internet: https://ir.wavelifesciences.com/static-files/24ab07d0-cc41-41f4-8cb0-b5c12363c186 ; Stand 30.08.2022
- 26 Wave Life Sciences Announces Initiation of Dosing in Phase 1b/2a SELECT-HD Clinical Trial of WVE-003 in Huntington’s Disease. Im Internet: https://www.globenewswire.com/news-release/2021/09/09/2294352/0/en/Wave-Life-Sciences-Announces-Initiation-of-Dosing-in-Phase-1b-2a-SELECT-HD-Clinical-Trial-of-WVE-003-in-Huntington-s-Disease.html; Stand 29.08.2022
- 27 Dale E, Frank-Kamenetsky M, Taborn K. et al. Stereopure Oligonucleotides for the Selective Silencing of Mutant Huntingtin (4703). Neurology 2020; 94: 4703
- 28 Spronck E, Vallès A, Lampen M. et al. Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology. Brain Sci 2021; 11: 129 DOI: 10.3390/brainsci11020129.
- 29 uniQure Announces Third Quarter 2022 Financial Results and Highlights Recent Company Progress. Im Internet: https://uniqure.gcs-web.com/node/10901/pdf; Stand 31.01.2023
- 30 uniQure Announces Update on Low-Dose Cohort in Phase I/II Clinical Trial of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease
- 31 Frank A, Bendig J, Schniewind I. et al. Serum neurofilament indicates that DBS surgery can cause neuronal damage whereas stimulation itself does not. Sci Rep 2022; 12: 1446 DOI: 10.1038/s41598-022-05117-x.
- 32 PTC518 Phase 1 Huntingtonʼs Disease Program Update (September 23, 2021). Im Internet: https://ir.ptcbio.com/static-files/2162ff85-c7ed-4555-8542-52fa2129f7fa; Stand 25.08.2022
- 33 Keller CG, Shin Y, Monteys AM. et al. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun 2022; 13: 1150 DOI: 10.1038/s41467-022-28653-6.
- 34 Sad news from Novartis: dosing suspended in VIBRANT-HD trial of branaplam. Im Internet: https://en.hdbuzz.net/328; Stand 01.11.2022
- 35 Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s Disease Im Internet: https://www.hda.org.uk/media/4418/novartis-vibrant-hd-community-letter-final-pdf.pdf; Stand 30.01.2023
- 36 Sangamo Therapeutics Corporate Presentation 2020. Im Internet: https://investor.sangamo.com/static-files/5a4f1add-fe7a-4c40-9580-5d45f750893a; Stand 25.08.2022
- 37 Zeitler B, Froelich S, Marlen K. et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat Med 2019; 25: 1131-1142 DOI: 10.1038/s41591-019-0478-3.
- 38 Virlogeux A, Moutaux E, Christaller W. et al. Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease. Cell Rep 2018; 22: 110-122 DOI: 10.1016/j.celrep.2017.12.013.
- 39 Sathe S, Ware J, Levey J. et al. Enroll-HD: An Integrated Clinical Research Platform and Worldwide Observational Study for Huntington’s Disease. Front Neurol 2021; 12: 667420 DOI: 10.3389/fneur.2021.667420.
- 40 Rodrigues FB, Owen G, Sathe S. et al. Safety and Feasibility of Research Lumbar Puncture in Huntington’s Disease: The HDClarity Cohort and Bioresource. J Huntingt Dis 2022; 11: 59-69 DOI: 10.3233/JHD-210508.
- 41 Tabrizi SJ, Schobel S, Gantman EC. et al. A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol 2022; 21: 632-644 DOI: 10.1016/S1474-4422(22)00120-X.