Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs

Dr. Oliver M. Dorchies, Pharmaceutical Biochemistry/Chemistry, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva

Abstract (Lay summary see below)

Muscular dystrophies (MDs) are a large group of debilitating muscular disorders of childhood or adulthood onset that can be fatal and for which no cure exists. Apart from the most frequent and most severe form, Duchenne muscular dystrophy (DMD), more than 80 forms are listed by Orphanet. As part of our recognized expertise with pre-clinical evaluation of active compounds in mouse models of DMD, we have published evidence that the inexpensive and safe anticancer drug tamoxifen (TAM) is extremely potent for counteracting dystrophic symptoms. These data, as well as on-going work in our lab, have identified enhancement of estrogenic signalling in muscle by selective estrogen receptor modulators (SERMs) as a novel therapeutic approach to the treatment of DMD but also of other MDs. We are committed in a 4-5-years research programme that aims at:
1- Exploring the roles of aromatase and estrogen receptors (ER) ERα, ERβ1 and ERβ2 in the progression of dystrophic symptoms and in TAM-mediated protection,
2- Investigating if TAM can prevent initial necrosis and enhance muscle regeneration in a mouse model of DMD,
3- Determining if TAM can prevent disease progression and increase survival time in mouse models of severe MDs other than mdx/DMD,
4- Screening, in the mdx dystrophic mouse, more than 15 SERMs and aromatase inhibitors (AIs)that are clinically approved for Human use,
5- Verifying the efficacy and safety of TAM and 2-3 short-listed SERMs in a dog model of DMD,
6- Setting a retrospective/prospective study about functional, biochemical and clinical outcomes in MD patients treated with SERMs and AIs because of concurrent hormonal disorders.
Our research programme is designed for time-efficient evaluation of clinically approved drugs that may reduce disease progression and improve the quality of life of patients with MDs, and to acquire greater understanding of the mechanisms that lead to the beneficial effects of such drugs.

Lay summary

Les dystrophies musculaires, dont la dystrophie musculaire de Duchenne (DMD) sont des  maladies rares invalidantes, voire fatales, actuellement sans traitement. Nous avons montré que le tamoxifène, un médicament anti-œstrogénique de la classe des SERM utilisé contre le cancer du sein, prévient efficacement la progression de la maladie chez la souris mdx, un modèle de DMD. Nos travaux suggèrent que la modulation de l’activité des œstrogènes par les SERMs constitue une piste thérapeutique pour la DMD et les dystrophies musculaires en général. Grâce au soutien financier de la FSRMM nous allons utiliser la souris mdx5Cv, modèle de la DMD pour :
1- Explorer le rôle des récepteurs des œstrogènes dans la progression de la maladie et la protection conférée par le tamoxifène
2- Etudier si le tamoxifène prévient la nécrose initiale et favorise la régénération musculaire
3- Evaluer une sélection de SERMs apparentés au tamoxifène et approuvés pour un usage humain
Enfin, nous utiliserons des souris modèles de dystrophies musculaires sévères pour :
4- Déterminer si le tamoxifène diminue leurs symptômes et augmente leur survie

Ce programme vise à identifier des médicaments qui peuvent réduire la progression de la maladie et améliorer la qualité de vie de patients souffrants de dystrophies musculaires.