Modelling Neuromuscular Diseases in the Age of Precision Medicine

Abstract

Advances in knowledge resulting from the sequencing of the human genome, coupled with technological developments and a deeper understanding of disease mechanisms of pathogenesis are paving the way for a growing role of precision medicine in the treatment of a number of human conditions. The goal of precision medicine is to identify and deliver effective therapeutic approaches based on patients’ genetic, environmental, and lifestyle factors. With the exception of cancer, neurological diseases provide the most promising opportunity to achieve treatment personalisation, mainly because of accelerated progress in gene discovery, deep clinical phenotyping, and biomarker availability. Developing reproducible, predictable and reliable disease models will be key to the rapid delivery of the anticipated benefits of precision medicine. Here we summarize the current state of the art of preclinical models for neuromuscular diseases, with particular focus on their use and limitations to predict safety and efficacy treatment outcomes in clinical trials.

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle

“…One reason for the limited number of available treatments is the lack of suitable humanized disease models that are able to mimic disease pathology and that allow the functional evaluation of novel therapeutic interventions [ 5 , 6 ]. Transgenic mouse models have been generated for many muscular dystrophies, but these often have mild phenotypes and may not (fully) represent disease mechanisms that operate in human patients due to species-specific differences [ 7 ]. It has therefore been difficult to translate results obtained in mouse models to human patients, resulting in a very low success rate of candidate drugs in clinical trials [ 7 ].…”

“…Transgenic mouse models have been generated for many muscular dystrophies, but these often have mild phenotypes and may not (fully) represent disease mechanisms that operate in human patients due to species-specific differences [ 7 ]. It has therefore been difficult to translate results obtained in mouse models to human patients, resulting in a very low success rate of candidate drugs in clinical trials [ 7 ]. In vitro systems for skeletal muscle include 2D cultures of differentiated human skeletal muscle cells, which provide an easy approach for the identification of therapeutic targets.…”

Modeling Patient-Specific Muscular Dystrophy Phenotypes and Therapeutic Responses in Reprogrammed Myotubes Engineered on Micromolded Gelatin Hydrogels

“…Alternatively, dermal fibroblasts derived from patient skin punches can be reprogrammed to induced pluripotent stem cells (iPSCs) and subsequently differentiated to myoblasts ( van der Wal et al, 2018 ). Although iPSC technology has led to useful models for DMD and other muscle disorders ( Caputo et al, 2020 ; Ortiz-Cordero et al, 2021 ), iPSCs can be difficult and costly to derive and expand ( Speciale et al, 2020 ). A simpler approach is to reprogram dermal fibroblasts directly to myoblasts by expression of MyoD, a master regulator of muscle cell development.…”

Urine-Derived Stem Cells Express 571 Neuromuscular Disorders Causing Genes, Making Them a Potential in vitro Model for Rare Genetic Diseases

“…Different cellular models have been characterized to improve molecular diagnosis and functional studies in these disorders. Currently procedures used to generate patient-specific cells such as myogenic cells, fibroblasts, and induced pluripotent stem cells (iPSCs) are mainly based on invasive methods (i.e., skin and muscle biopsies) ( Speciale et al, 2020 ). Increased attention has been focused on stem cells derived from urine specimens (USCs) that now are used in a broad field of applications and, in some cases, are replacing the traditional cell sources obtained with invasive and time-consuming methods ( Falzarano and Ferlini, 2019 ).…”