DISEASE

Modelling

& Therapies

OVERVIEW

There are very few treatments available for individuals with rare genetic muscle diseases. To address this unmet need, our team is working to design and test new treatments for congenital myopathies caused by pathogenic variants in a subset of muscle genes. We are also developing new patient-derived cell models, and refining methods for screening the effectiveness of these new treatments at the pre-clinical level.

The ultimate goal of the Disease Models and Therapies Team is to develop safe and effective treatments for rare and (currently) incurable genetic muscle diseases.

There are very few treatment options available for patients, and these are available only for a small handful of the many different rare neuromuscular diseases. We want to develop treatments so that more patients have options available to them, beyond management of symptoms. In order to achieve this, we first need suitable cell platforms that can be used to test the effectiveness of new treatments. Therefore, we are also developing new ways to model muscle diseases in a dish.

DESIGNING AND TESTING NEW TREATMENTS FOR MUSCLE DISEASE

We are working on a range of targeted treatments that address the underlying cause of genetic muscle diseases. These treatments include genome engineering (CRISPR/Cas9) and antisense oligonucleotides (AONs). We collaborate with world leading scientists and use a range of cutting-edge technologies to design and test our patient-centric treatments. For example, we are working with W/Prof. Sue Fletcher, AO, who is a member of the team that pioneered the use of AONs as a treatment for Duchenne muscular dystrophy.

We are currently in the early pre-clinical stages of screening our novel treatments and there is still plenty of work to do in this space! Over the coming years we hope to establish a roadmap for developing, screening, and translating new treatments. The ultimate goal of the Disease Models and Therapies team is to provide urgently needed treatments to as many rare disease patients as possible.

Staining of untreated and treated mousemuscle demonstrating pre-clinical treatment efficacy of a novel gene therapydeveloped by our team. Image modified from McNamara and Taylor et al. (2020)Hum Mol Genet. 1;29(1):20-30. doi: 10.1093/hmg/ddz214.

Making muscle cells from patient blood

As an (almost) unlimited source of patient material, we take the patient’s own blood cells (ethically derived and minimally invasive) and turn them into a different cell type called an induced pluripotent stem cell (iPSC). We then turn the iPSCs into muscle cells since these are a disease-relevant cell type. Patient-derived muscle cells can then be grown in a single layer (called 2D culture) and used to advance our research, by modelling the features of the disease in a dish. We are actively exploring relevant disease biology using bulk transcriptomic, proteomic, single cell and single nuclei approaches on patient derived cells, as well as control cells and a range of tissues. We also use these muscle cells in 2D as our first line of screening for new treatments we are developing (see/link tab above).

Cultured cells are an extremely useful resource but do have limitations in 2D since they are not identical to the more complex skeletal muscle in our bodies that allows us to move, eat and breath. Therefore, we are also establishing engineered skeletal muscle organoids in 3D (see/link tab above).

Although cultured cells are incredibly useful for understanding disease, muscle cells grown in a flat (2D) layer are quite far removed from a functional tissue. Specifically, fused muscle cells (myotubes) require mechanical forces such as tension and electrical stimulation (e.g. via nerve cells) for proper development and maturation.

In our team, we use the “Mantarray” platform to create functional 3D engineered muscle tissues (EMTs) using human muscle cells. EMTs can be stimulated to contract using electrical stimulation (mimicking a nerve impulse). We can then measure the force output, contraction and relaxation dynamics and more – crucial aspects for the study of muscle diseases. EMTs can also be harvested to interrogate structural, metabolic and molecular changes. Overall, 3D EMTs provide a pre-clinical system we can use to model disease and test treatments using patient-derived cells.

We are currently investigating the utility of the Mantarray for modelling patient-relevant features in a subset of our healthy-control and patient-derived cell lines.