20 years of pharmacotherapy for Duchenne Muscular Dystrophy: From mouse models to patients… and back

Description

Abstract Duchenne muscular dystrophy (DMD) is a rare genetic disease due to the absence of dystrophin from striated muscles. Affected boys suffer from progressive muscle wasting. Despite improved medical care, most patients die before their 30s due to cardiac and respiratory failure. For almost 40 years, DMD has been the focus of intense preclinical research, using a variety of dystrophic mouse models that all lack functional dystrophin: the main lines are mdx, mdx5Cv, and more recently D2.mdx. Hundreds of reports have been published that demonstrate impressive efficacy of diverse therapeutic interventions in dystrophic mice, leading to huge hope in families afflicted with DMD. However, most of these promising therapies show little efficacy, if any, in subsequent clinical trials in DMD patients. At present, lack of preclinical to clinical translation is a major obstacle to the development of efficacious therapy for DMD. It is largely accepted that the poor clinical translation results from a much milder phenotype, disease progression and life expectancy in dystrophic mice compared to patients.

We will give an overview of our contribution to pharmacotherapy for DMD over the last 20 years. Emphasis will be made on tamoxifen, including the long preclinical path and the outcome of the ensuing clinical trial TAMDMD. Then, we will present our current work for developing more reliable models of DMD towards more predictable outcomes in clinical trials. To this aim, we are exploring the roles of the susceptibility gene Ltbp4: Ltbp4DEL mutation is naturally present in the DBA/2J genetic background and is thought to enhancefibrosis and atrophy in D2.mdx mice, as in DMD patients. However, no effect was observed after transfer of Ltbp4DEL into mdx5Cv mice in the C57BL/6J background. These findings question the roles of Ltbp4 in DMD and its value to aggravate the phenotype of mice.

In parallel, we have developed the FU-5Cv dystrophic line, which allows to downregulate utrophin (a dystrophin homologue upregulated in dystrophic muscle) in skeletal muscle only. This model showed impaired muscle function and force, enhanced fibrosis and muscle wasting, and a shorter lifespan. All these outcomes reveal an aggravated dystrophic phenotype and make the FU-5Cv mouse line a better DMD-like model. Finally, we will introduce manipulation of the utrophin promoter to reduce utrophin overexpression in muscles of dystrophic mice while sparing expression in other tissues and at the neuromuscular junction.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Henzi BC, Schimdt S, Nagy S, Rubino-Nacht D, Schaedelin S, Putananickal N, Amthor H, Childs A-M, Deconinck N, de Groot I, Horrocks I, Houwen-van Opstal S, Laugel V, Lopez Lobato M, Madruga Garrido M, Nascimento Osorio A, Schara-Schmidt U, Spinty S, von Moers A, Lawrence F, Hafner P, Dorchies OM, Fischer D. Lancet Neurol.22(10):890-899 (2023). doi: 10.1016/S1474-4422(23)00285-5

Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies. Djeddi S, Reiss D, Menuet A, Freismuth S, de Carvalho Neves J, Djerroud S, Massana-Muñoz X, Sosson AS, Kretz C, Raffelsberger W, Keime C, Dorchies OM, Thompson J, Laporte J. Mol Ther, 29(8):2514-2534 (2021). doi: 10.1016/j.ymthe.2021.04.033

Le tamoxifène dans l’arsenal thérapeutique des maladies neuromusculaires ? . Dorchies OM, Brignol TN. Cah Myol. 19, 25-27 (2019).

Repurposing the selective oestrogen receptor modulator tamoxifen for the treatment of Duchenne muscular dystrophy. Gayi E, Neff LA, Ismail HM, Ruegg UT, Scapozza L, Dorchies OM. Chimia (Aarau). 72(4), 238-240 (2018). doi: 10.2533/chimia.2018.238

The potential and benefits of repurposing existing drugs to treat rare muscular dystrophies. Ismail HM, Dorchies OM, Scapozza L. Exp Opin Orphan Drugs. 6(4), 259-271 (2018). doi.org/10.1080/21678707.2018.

Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Gayi E, Neff LA, Massana Muñoz X, Ismail HM, Sierra M, Mercier T, Décosterd LA, Laporte J, Cowling BS, Dorchies OM, Scapozza L. Nat Commun. 9(1), 4848 (2018). doi: 10.1038/s41467-018-07058-4

The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy. Dorchies OM, Reutenauer-Patte J, Dahmane E, Ismail HM, Petermann O, Patthey- Vuadens O, Comyn SA, Gayi E, Piacenza T, Handa RJ, Décosterd LA, Ruegg UT. Am J Pathol. 182(2):485-504 (2013). doi: 10.1016/j.ajpath.2012.10.018