Inhibition of sphingolipid synthesis as a treatment strategy for Duchenne muscular dystrophy

Prof. Johan Auwerx, EPFL, Lausanne

Abstract (lay summary see below)

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and affects 1 in 3500 newborn boys. At present, no curative treatment for DMD is available. Even if CRISPR/Cas9-mediated gene editing seems very promising, it is unlikely to provide a cure for all patients, given the allelic heterogeneity of the disease. Thus, for a significant proportion of DMD patients, new treatments are needed to improve their prognosis.

Building on decades of expertise in metabolic and translational research (e.g. our discovery of NAD+ depletion to be involved in both age-related muscle-dysfunction and DMD, and that NAD repletion could improve muscular fitness in both conditions (1,2) ), we now aim to study the biological pathways underlying the pathophysiology of DMD, and the suitability of these pathways for pharmacological interventions. These pathways include 1) sphingolipid metabolism; and 2) mitochondrial proteostasis.

We recently discovered that sphingolipid de novo synthesis is upregulated upon aging, and that pharmacological inhibition of this pathway restores muscle function in sarcopenia (Laurila, submitted). Our latest experiments revealed that the sphingolipid synthesis pathway is also overexpressed in DMD and several other muscular dystrophies. Therefore, we aim to study whether inhibition of sphingolipid synthesis could also improve the course and symptoms of DMD, as it did in sarcopenia. We will test pharmacological inhibitors of sphingolipid de novo synthesis in different mouse models relevant to DMD. Since depletion of muscle stem cells (MuSC) is a hallmark of DMD, and sphingolipid depletion improves MuSC function (Laurila, submitted), we will focus here on mechanistically characterizing the role of sphingolipid synthesis inhibition on MuSCs in DMD. As we have discovered dysregulation of mitochondrial proteostasis pathways in muscular dystrophies and in age-related sarcopenia (Romani, submitted), we will also examine the role of sphingolipids in proteostatic imbalance, and study whether inhibition of sphingolipid de novo synthesis could restore defective proteostasis characteristic of DMD.

Our proposal, building on the translational expertise of our laboratory in muscular diseases, and on our in-depth understanding of sphingolipid metabolism and mitochondria, provides a strong basis to discover novel pathophysiological mechanisms behind myopathies and examine their potential as treatment targets for DMD.

Lay summary

Duchenne Muskeldystrophie (DMD) ist mit 1/3500 befallenen neugeborenen Jungen die häufigste Muskeldystrophie, für welche es derzeit keine Behandlung gibt.

Fehlfunktion der Muskelstammzellen ist ein Kennzeichen von DMD und wir konnten neulich zeigen, dass mitochondrialer Proteinstoffwechsel ebenso dysfunktional ist (Romani et al., submitted). Interessanterweise könnte Sphingolipidmetabolismus der gemeinsame Nenner dieser Fehlfunktionen sein. Wir haben entdeckt, dass de novo Sphingolipidsynthese erhöht ist in DMD, und, dass dessen Hemmung in Sarkopenie zu verbesserten Muskelstammzellen, Proteinstoffwechsel und Muskelfunktion führt (Laurila et al., submitted). Deshalb wollen wir jetzt untersuchen, ob pharmakologische Hemmung der Sphingolipidsynthese auch die Fehlfunktion der Muskelstammzellen und des Proteinstoffwechsels in DMD korrigiert, und damit Krankheitssymptome verbessern kann.

Unser Antrag basiert auf Translationsexpertise sowie unser detailliertes Verständnis von Sphingolipidmetabolismus und Mitochondrien, und bietet eine starke Grundlage zur Entdeckung einer neuen Behandlungen für DMD.