Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin.

Effects of HMGCR deficiency on skeletal muscle development

“…Abnormal lipid profiles have been observed in humans with dystrophinopathy 38 and dysferlinopathy 39 . Statin therapy does not appear to be a viable primary or adjunctive therapy for muscular dystrophy, as confirmed in multiple mouse studies [39][40][41][42] . However, the non-statin cholesterol-lowering agent ezetimibe showed promise in mouse models of dystrophinopathy and dysferlinopathy 43 .…”

Deciphering the Molecular Mechanism of Incurable Muscle Disease by a Novel Method for the Interpretation of miRNA Dysregulation

“…Meanwhile, a very recent study by another group supports a central role of cholesterol metabolism in DMD [ 45 ]. In ongoing investigations by our group, we attempted, with limited success, to translate this discovery into an improved therapeutic protocol in a preclinical model for DMD [ 46 ]. Concerning the host gene method for the biological interpretation of miRNA dysregulation, cross-validation of its performance is required by other groups, in other experimental systems.…”

An integrin-targeting AAV developed using a novel computational rational design methodology presents improved targeting of the skeletal muscle and reduced liver tropism

“…Severe toxicities, even patient death, have been reported from these trials (NCT03368742, NCT04281485), assumed to be related to the dose of ≥ 1E14 vg/kg. We therefore explored the possibility of low-dose µDys gene transfer 41 LICA1 showed better µDys gene transfer than AAV9 in this model. LICA1-treated mice exhibited a signi cantly higher VCN in all 3 muscles that were tested, 1.85/2.02/1.07 times higher in TA (p < 0.0001), Qua (p < 0.0001), and Dia (p = 0.020), respectively (Fig.…”

“…This nding highlights the importance of selecting an appropriate targeting receptor for rational design and further supports αVβ6 as a promising candidate for targeting skeletal muscle. LICA1 is a potential vector for muscular diseases AAV gene therapy in muscle diseases typically requires very high doses (≥ 1E14 vg/kg) for functional bene ts 41,46 , yet can result in severe and even fatal adverse events 7 . In this study, we explored low dose (5E12 vg/kg) treatment using the LICA1 vector in two MD mouse models, DMD and LGMDR3.…”