Neurology Research Groups

Research Aims & Objectives

The overall theme of my research is ‘RNA Medicine’ with the following key focus areas:

• Development of novel RNA-based and RNA-targeting therapeutics.
• Discovery and development of RNA Biomarkers for neuromuscular disorders.
• The study of gene expression, regulation and sub-cellular organisation in the pathogenesis of diseases such as Duchenne muscular dystrophy (DMD).

Details of research interests

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting condition that is caused by loss-of-function mutations in the gene encoding dystrophin, a molecular ‘shock absorber’ that protects myofibres from contractile damage. The dystrophin gene is the largest in the genome, and contains many semi-redundant internal domains. It is therefore amenable to splice correction therapy (i.e. exon skipping) whereby mRNA splicing is modulated so as to restore the translation reading frame of the mutant dystrophin transcript. To this end, our group has demonstrated enhanced exon skipping activity using peptide-conjugated morpholino oligonucleotides (PPMO). More recently, we have explored the possibility of using CRISPR/Cas9-mediated gene editing in order to achieve ‘permanent exon skipping’ in dystrophic mice.

Characterising gene expression events occurring in dystrophic muscle is crucial for understanding the molecular pathology of DMD, discovering biomarkers, and identifying novel therapeutic targets. We have utilised various transcriptomics and proteomics techniques to further this goal.

Of particular interest are the microRNAs (miRNAs), a class of small non-coding RNAs that are involved in gene regulation. miRNAs have been implicated in multiple pathological features of DMD including fibrosis, regeneration and the regulation of dystrophin expression. Specific miRNAs are also elevated in the serum of DMD patients and animal models. Our group has extensively studied extracellular miRNAs, demonstrating that they are pharmacodynamic biomarkers of exon skipping therapy, and reflect muscle turnover. Furthermore, we have recently utilised miRNA biomarkers to identify dystrophin uniformity as a key determinant of therapeutic success.

Given that serum is a hostile environment for RNA molecules, we have investigated the stability of extracellular miRNAs. Notably, the majority of extracellular miRNAs are stabilised in protein complexes, with only a small proportion present in Extracellular Vesicles (EVs). The potential for extracellular miRNAs to act as signalling molecules between cells in skeletal muscle is an area of ongoing investigation.

Our group is also interested in the application of genomics techniques to identify novel RNA regulatory motifs, that can be targeted using oligonucleotide approaches. We are developing oligonucleotides with novel mechanisms-of-action with the aim of treating a variety of disorders with an initial focus on infantile epileptic encephalopathies.

Group Leader

Thomas Roberts

Group Members

Postdoctoral Researchers:

• Dr Katarzyna Chwalenia
• Dr Ning Feng

Research Assistant:

• Nina Ahlskog

DPhil Students:

• Junyu 'Jerry' Huang
• Angus Lennaárd Johansson
• Aimee Ruffle (with NDCLS)
• Nicole Schafer
• Gavin Turnbull (with NDCLS)

Master's Students:

• Helen Adam, Freie Universität Berlin
• Alysia Martinez

Former Members:

• Dr Sofia Stenler
• Dr Yulia Lomonsova
• Dr Rushdie Abuhamdah

Completed DPhil Students:

• Dr Anna Coenen-Stass (2016)
• Dr Tirsa van Westering (2018)
• Dr Britt Hanson (2021)
• Dr Nenad Svrzikapa
• Dr Carla Martin Perez
• Dr Katarzyna Chwalenia

Completed Master's Students:

• Thomas Goedert

Previous Visiting Students:

• Nicole Hemmer (MSc), Universität Tübingen
• Vivi-Yun Feng (MSc), Freie Universität Berlin

Collaborators

Collaborators - Oxford:

• Prof Deborah Gill (Radcliffe Department of Medicine, Oxford, UK)

Collaborators - External:

• Prof Samir EL Andaloussi (Karolinska Institutet)
• Prof Annemieke Aartsma-Rus (Leiden University Medical Center, NL)
• Prof Mikko Turunen (University of Eastern Finland)
• Prof Minna Kaikkonen-Määttä (University of Eastern Finland)
• Prof Yoshitsugu Aoki (NCNP, Tokyo, Japan)
• Prof Eric Wang (University of Florida)
• Prof Janne Lehtiö (Karolinska Institutet)
• Prof David Tollervey (University of Edinburgh)

Funders

• Muscular Dystrophy UK
• MRC
• Duchenne Parent Project NL
• Great Ormond Street Hospital Children’s Charity
• Dravet Syndrome UK
• OUP John Fell Fund
• Medical and Life Sciences Translational Fund
• University Challenge Seed Fund