Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

Abstract

Muscular Dystrophies (MDs) are a group of rare inherited genetic muscular pathologies encompassing a variety of clinical phenotypes, gene mutations and mechanisms of disease. MDs undergo progressive skeletal muscle degeneration causing severe health problems that lead to poor life quality, disability and premature death. There are no available therapies to counteract the causes of these diseases and conventional treatments are administered only to mitigate symptoms. Recent understanding on the pathogenetic mechanisms allowed the development of novel therapeutic strategies based on gene therapy, genome editing CRISPR/Cas9 and drug repurposing approaches. Despite the therapeutic potential of these treatments, once the actives are administered, their instability, susceptibility to degradation and toxicity limit their applications. In this frame, the design of delivery strategies based on nanomedicines holds great promise for MD treatments. This review focuses on nanomedicine approaches able to encapsulate therapeutic agents such as small chemical molecules and oligonucleotides to target the most common MDs such as Duchenne Muscular Dystrophy and the Myotonic Dystrophies. The challenge related to in vitro and in vivo testing of nanosystems in appropriate animal models is also addressed. Finally, the most promising nanomedicine-based strategies are highlighted and a critical view in future developments of nanomedicine for neuromuscular diseases is provided.

Keywords: CRISPR/Cas9; Duchenne Muscular Dystrophy; antisense oligonucleotides; myotonic dystrophy; nanoparticles; small molecules.

Figure 1

Schematic representation of the pathogenesis of both Myotonic Dystrophies and Duchenne Muscular Dystrophy. (DM1: Myotonic Dystrophy type 1; DM2: Myotonic Dystrophy type 2.)

Figure 2

Organization of the skeletal muscle tissue and the target-tissue related to the class of experimental molecules (ASO, antisense oligonucleotide; CRISPR, clustered regularly interspaced short palindromic repeats).

Figure 3

Work flow for the design of innovative nanomedicine and therapeutic readout. (ASOs, antisense oligonucleotides; CRISPR, clustered regularly interspaced short palindromic repeats).

Figure 4

Strategies and accurate models to explore MD treatments. Broad in vitro, ex vivo and in vivo MD models to promote the translation of nanomedicine-based therapies (MD, muscular dystrophies; X-MET, ex vivo-vascularized muscle engineered tissue).