Nanotherapy for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy.

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

“…At the cellular level, the muscles of DMD patients show evidence of necrosis, degeneration and regeneration, myofiber atrophy, fatty accumulation, fibrosis, and inflammation (Spencer and Tidball, 2001 ; Alvarez et al, 2002 ; Desguerre et al, 2009a , b ; Serrano and Muñoz-Cá-noves, 2010 ; Zhou and Lu, 2010 ; Villalta et al, 2011 ). Different approaches (gene-based, cell-based, nano-particles, and pharmacological) have been developed to restore a functional dystrophin to DMD muscles (Negroni et al, 2016 ; Chamberlain and Chamberlain, 2017 ; Nance et al, 2017 ). These strategies are promising and several clinical trials are on-going or have been conducted on DMD patients: between 1995 and 2018, 127 clinical trials are found on clinicaltrials.gov, with 57% pharmacological approaches, 28% gene-based (22% antisense oligonucleotide based exon skipping, 6% AAV gene addition), and 3% cell-based approaches.…”

Advance in Drug Delivery for Ageing Skeletal Muscle

“…Reproduced, with permission, from . Li et al Drug Delivery for Ageing Muscle (Nance et al, 2018;Nag et al, 2020). For example, Poussard, S et al observed the silica nanoparticles uptake by myoblasts and promote the differentiation in vitro (Poussard et al, 2015).…”

“…The growing concern of nanoparticles is triggered by the rapid development of nanotechnology. Nanoparticles have many unique advantages including enhanced tissue targeting, nucleic acids protection from degradation, and low immunogenicity ( Nance et al., 2018 ; Nag et al., 2020 ). For example, Poussard, S et al.…”

Hexose Potentiates Peptide-Conjugated Morpholino Oligomer Efficacy in Cardiac Muscles of Dystrophic Mice in an Age-Dependent Manner

“…A myriad of strategies to enhance the systemic delivery efficiency of AOs has been under scrutiny, including the use of cell-penetrating peptides (CPPs), nanoparticles, viruses, and small compounds 5, 6. Among them, CPPs led the way due to advantages such as small molecular weight and high membrane permeabilization capacity; however, the safety profiles present a hurdle for their clinical translation 7 .…”