Construction of a conceptual framework that integrates phenotypic, cellular and molecular data in DM is a critical step in developing a robust and diverse pipeline of candidate therapies. Although basic science has mechanistically linked the inherited repeat expansions to DM1 and DM2 phenotypes, there are critical gaps in understanding of disease mechanisms. A recent publication extends our understanding.

Dr. Perrine Castets, Prof. Michael Sinnreich and colleagues at the University of Basel recently studied the notion that perturbation of skeletal muscle metabolic pathways, including those responsible for protein degradation (ubiquitin-proteasome system and autophagy), plays an important role in DM. Their results, published in the Journal of Clinical Investigation, establish that (a) DM1 muscle is characterized by an altered response to energy/nutrient deprivation and that (b) dysregulation of AMPK/mTORC1 signaling, at least in part, underlies the altered metabolic state and its role in the pathogenesis of DM1 skeletal muscle. Importantly, these findings suggest new targets for drug discovery and development.

In studies of the HSALR mouse model of DM1, the investigators showed that a normal molecular response to fasting, AMPK activation and mTORC1 inhibition, is compromised in HSALR mice. Consistent with these findings and the interrelated role of AMPK and mTORC1 in autophagy, experimentally induced autophagy was disrupted in HSALR muscle. Deprivation of energy and nutrient supply in DM1 patient myotubes also produced data consistent with dysregulated autophagy. Finally, targeting either AMPK (with AICAR) or mTORC1 (with rapamycin) signaling improved muscle strength, splicing and/or myotonia in HSALR mice.

While the AMPK agonist, AICAR, disrupted nuclear foci and reduced myotonia, along with partial normalization of splicing (correction of Clcn1, but not Atp2a1 and Camk2b) in HSALR mice, rapamycin’s, an mTORC1 inhibitor, normalization of muscle function was not accompanied by correction of mis-splicing.

Many of the therapeutic strategies under development for DM are based on restoration of dysregulated alternative splicing. The study by the University of Basel group further supports those strategies, but also characterizes a key metabolic defect in DM1 muscle and identifies the mTORC1 pathway as an alternative, splicing-independent target for therapy development.

Thus far, nearly all of the therapy development programs in DM address the muscle phenotype. Recent studies show that the mTOR pathway may be an important target in developmental intellectual disorders, and two mTOR inhibitors have regulatory approval for other indications (Novartis' Everolimus and Wyeth's Sirolimus (rapamycin)). Drugs targeting mTORC1 then may have efficacy for both the skeletal muscle and cognitive symptoms of DM1 and thus their potential should be explored via rigorous efficacy studies in appropriate preclinical models.

Reference:

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.
Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, Frank S, Angelini C, Furling D, Rüegg MA, Sinnreich M, Castets P.
J Clin Invest. 2017 Jan 9. pii: 89616. doi: 10.1172/JCI89616. [Epub ahead of print