Human skeletal muscle platform for disease modelling and high-throughput drug screening

Introduction

Neuromuscular disorders (NMDs) are a collection of pathologies that affect the skeletal muscle (SkM) function and lead to reduced mobility, breathing issues, and death. Most NMDs are incurable, and existing therapies are generally ineffective.

Challenges in NMD Therapy Development

The major contributor to the lack of NMD therapies is the absence of human NMD research models, applicable for the screening and validation of therapeutic candidates.

Project Goals

Our goal for this project is to develop an in vitro platform containing highly biomimetic and functional SkM analogues, where NMDs can be modeled with the aim of testing drug candidates in a reliable, high-throughput (HT), and quick manner.

Platform Design

The platform will consist of 96 individual 3D tissue units, generated from the myogenic differentiation of human induced pluripotent stem cells (hiPSCs). To induce biomimetic and mature tissue formation, the platform will combine:

• A unique topographical design
• A light-stimulation system for optogenetic control of SkM contraction

Methodology

Using image-based assays and computational algorithms, we will be able to automatically extract and quantify the SkM phenotypical (e.g., intracellular structure) and functional (e.g., contraction speed/force) parameters.

NMD Modeling

To demonstrate NMD modeling ability within the platform, we will knockout BIN1, a gene whose mutated form is involved in the onset of centronuclear myopathy (CNM), a fatal and incurable NMD. The validity of the NMD model as a drug discovery platform will be demonstrated by testing compounds with known therapeutic activity.

Future Implications

This proof of concept project will lay the groundwork for a spin-off company devoted to HT drug screening for NMDs.

Conclusion

The successful development of this platform will provide an invaluable tool for pharmaceutical research, allowing accurate, convenient, and cost-effective identification of novel drugs and therapeutic targets for NMDs, ultimately contributing to the acceleration of novel therapies for NMD patients.