Molekulare Therapien erblicher Myopathien im Erwachsenenalter – eine kursive Rundschau

Zusammenfassung

Unterschiedliche Formen der molekularen Therapie sind zu einer neuen Möglichkeit in der Präzisionsbehandlung erblicher neuromuskulärer Erkrankungen geworden. Dieser kursive Überblick über die molekularen Therapien bei hereditären Myopathien wird sich auf ausgewählte aktuelle Phase 1 bis 3 Studien zu häufigen hereditären Myopathien im Erwachsenenalter wie die Dystrophinopathie Becker-Kiener, die Fazioskapulohumerale Muskeldystrophie, Calpainopathie, und die Dysferlinopathie fokussieren. Die Therapieoptionen zum Morbus Pompe dienen als Beispiel für die hereditären metabolischen Myopathien.

Abstract

Several types of molecular therapy have become a novel opportunity in the precision treatment of hereditary neuromuscular disorders. This cursive review of gene therapy in hereditary myopathies will focus on selected current phase 1 to 3 trials of common adult hereditary myopathies such as Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, calpainopathy, and dysferlinopathy. The treatment options for Pompe disease serve as an example for hereditary metabolic myopathies.

Schlüsselwörter

Molekulare Therapie - klinische Studien - erbliche Myopathien - Neuromuskuläre Erkrankungen - Überblick

Key words

molecular therapy - clinical trials - hereditary myopathy - neuromuscular disorders - review

Publikationsverlauf

Eingereicht: 28. Juli 2022

Angenommen: 23. September 2022

Artikel online veröffentlicht:
08. November 2022

• Literatur

• 1 Schoser B. Prinzipien der translationalen Gentherapie für neuromuskuläre Erkrankungen. Nervenarzt 2022; 93: 537-548
• 2 Sun C, Shen L, Zhang Z, Xie X. Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes 2020; 11
• 3 Angelini C, Marozzo R, Pegoraro V. Current and emerging therapies in Becker muscular dystrophy (BMD). Acta Myol 2019; 38: 172-179
• 4 https://musculardystrophynews.com/news/trial-becker-md-treatment-edg-5506-enrolling-patients/ zuletzt aufgerufen 23.07.2022
• 5 Mah JK, Clemens PR, Guglieri M. et al. Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy. A 30-Month Nonrandomized Controlled Open-Label Extension Trial. JAMA Netw Open 2022; 5: e2144178
• 6 Schätzl T, Kaiser L, Deigner HP. Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update. Orphanet J Rare Dis 2021; 16: 129
• 7 Rojas LA, Valentine E, Accorsi A. et al. p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy. J Pharmacol Exp Ther 2020; 374: 489-498
• 8 Mellion ML, Ronco L, Berends CL. et al. Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement. Br J Clin Pharmacol 2021; 87: 4658-4669
• 9 Straub V, Murphy A, Udd B. LGMD workshop study group. 229th ENMC international workshop: Limb girdle muscular dystrophiesNomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord 2018; 28: 702-710
• 10 Angelini C, Fanin M. Calpainopathy. 2005 May 10 [updated 2017 Aug 3]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301490
• 11 Bartoli M, Roudaut C, Martin S. et al. Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A. Mol Ther 2006; 13: 250-259
• 12 Sahenk Z, Ozes B, Murrey D. et al. Systemic delivery of AAVrh74.tMCK.hCAPN3 rescues the phenotype in a mouse model for LGMD2A/R1. Mol Ther Methods Clin Dev 2021; 22: 401-414
• 13 Selvaraj S, Dhoke NR, Kiley J. et al. Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy. Mol Ther 2019; 27: 2147-2157
• 14 Rico A, Guembelzu G, Palomo V. et al. Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related. Int J Mol Sci 2021; 22: 7367
• 15 Bittel DC, Screetama SC, Chandra G. et al. Jaiswal Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B. J Clin Invest 2022; 132: e141295
• 16 Chandra G, Sreetama SC, Mázala DAG. et al. Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair. J Cell Biol 2021; 220: e202006035
• 17 Schüller A, Wenninger S, Strigl-Pill N, Schoser B. Toward deconstructing the phenotype of late-onset Pompe disease. Am J Med Genet C Semin Med Genet 2012; 160C: 80-88
• 18 Gutschmidt K, Musumeci O, Díaz-Manera J. et al. STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa. J Neurol 2021; 268: 2482-2492
• 19 Diaz-Manera J, Kishnani PS, Kushlaf H. et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol 2021; 20: 1012-1026
• 20 Schoser B, Roberts M, Byrne BJ. et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol 2021; 20: 1027-1037
• 21 Stok M, de Boer H, Huston MW. et al. Lentiviral hematopoietic stem cell gene therapy corrects murine Pompe disease. Mol Ther Methods Clin Dev 2020; 17: 1014-1025
• 22 Piras G, Montiel-Equihua C, Chan YA. et al. Lentiviral hematopoietic stem cell gene therapy rescues clinical phenotypes in a murine model of Pompe disease. Mol Ther Methods Clin Dev 2020; 18: 558-570
• 23 Clayton NP, Nelson CA, Weeden T. et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 Synthesis as an approach for substrate reduction therapy of Pompe disease. Mol Ther Nucleic Acids 2014; 3: e206
• 24 Liang Q, Vlaar EC, Catalano F. et al. Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease. Mol Ther Methods Clin Dev 2022; 25: 520-532
• 25 Unnisa Z, Yoon JK, Schindler JW, Mason C, van Til NP. Gene Therapy Developments for Pompe Disease. Biomedicines 2022; 10
• 26 Tang B, Frasinyuk MS, Chikwana VM. et al. Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase. J Med Chem 2020; 63: 3538-3551