The therapeutic potential of targeting RNA

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. Symptoms include muscle weakness and wasting, cataracts, diabetes, and irregular heartbeat. DM is an inherited condition that exists in two forms: DM1 and DM2. Both are caused by a different piece of faulty DNA. Recent experiments point to a common mechanism underlying both forms of DM. In both forms of DM the faulty DNA is made into RNA but this gets stuck in the nucleus and can be seen down the microscope as spots in the cells of DM patients. We have shown that three particular proteins, called muscleblind proteins, are present in the spots in DM cells. We aim to develop methods to study the faulty RNA, which will allow the development of assays or tests for drugs to treat the disorder. It is possible that the methods developed here may be applied to other human disorders.

Technical Summary

Myotonic Dystrophy (DM) is the most common form of muscular dystrophy affecting adults. Symptoms include muscle weakness and wasting, myotonia, cardiac arrhythmias, diabetes, cataracts and premature balding in men. Two different mutations cause this condition. In 98 per cent of patients the disease is associated with a triplet repeat (CTG) expansion in the 3? untranslated region of the DMPK gene (DM1). In two percent the underlying mutation is a tetranucleotide (CCTG) expansion in an intron of the gene ZNF9 (DM2). In both cases the faulty gene is transcribed but the mutant RNA is trapped in the nuclei of DM cells, forming foci, which sequester muscleblind-like proteins. We propose a series of experiments to examine synthetic repeat-containing RNAs and in-vitro transcribed repeat expansion RNAs. We will produce the mutant RNAs and label them, and interacting molecules, using fluorophores to establish the methods to screen in vitro for compounds that may be useful as a therapy for DM. We hope to extend this work in the future to other mutant RNAs in human disease.
 
Description Hermes funding for commercial exploitation UoN
Amount £48,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 02/2017
 
Description Leverhulme Research Fellowship
Amount £45,000 (GBP)
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 03/2012
 
Description Seeding Drug Discovery
Amount £3,124,782 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 01/2018
 
Title chemically modified oligonucleotides 
Description Multiple chemically modified oligonucleotides have been developed and tested in cell-based assays for their effectiveness. Progress has been achieved and this work is ongoing. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact No impacts to report, but we are only 12 months in to the project. 
 
Description DM Therapy with GSK 
Organisation GlaxoSmithKline (GSK)
Department Research and Development GSK
Country United Kingdom 
Sector Private 
PI Contribution We have performed screens with reagents generated by GSK
Collaborator Contribution A member of my lab worked at GSK for 3 months and they actioned a proteomics screen by Cellzome.
Impact None yet
Start Year 2011
 
Description Developing a drug to treat myotonic dystrophy 
Organisation Argenta Discovery
Country United Kingdom 
Sector Private 
PI Contribution We are trying to identify a drug to treat myotonic dystrophy in collaboration with Argenta Discovery. We have developed an assay which we are using to test compounds generated by Argenta.
Collaborator Contribution Argenta Discovery is a Med Chem company developing small molecules that we test.
Impact None yet
Start Year 2016
 
Description Drug development for myotonic dystrophy 
Organisation Charles River Laboratories
Country United States 
Sector Private 
PI Contribution Nuclear foci assay of DM cells
Collaborator Contribution Medicinal Chemistry for drug development
Impact None yet, but patent filed
Start Year 2015
 
Description Kinome profiling with Cellzome 
Organisation GlaxoSmithKline (GSK)
Department Cellzome Ltd
Country Germany 
Sector Private 
PI Contribution We provided protein extracted from myotonic dystrophy patient cell lines
Collaborator Contribution The Cellzome collaborators provide kinobead proteomic analysis.
Impact Paper submitted. Outcome pending
Start Year 2013
 
Description in vivo testing of oligonucleotides 
Organisation University of Nottingham
Department Cancer Biology Unit
PI Contribution The oligonucleotides we developed have now been tested in vivo
Collaborator Contribution Dr Anna Grabowska brings in vivo imaging expertise to the project
Impact No outputs yet
Start Year 2017
 
Description IDMC10 Paris 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation to lay group and professionals
Year(s) Of Engagement Activity 2015
 
Description IDMC9 San Sebastian, Spain 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The meeting was attended by 250 scientists working on DM.

Positive feedback from other scientists.
Year(s) Of Engagement Activity 2013
 
Description Identification of a novel kinase target in Myotonic Dystrophy type 1. The Human Genome and Healthcare Meeting, Royal Society, London, 23rd November 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at a scientific meeting followed by Q & A.
Year(s) Of Engagement Activity 2017
 
Description Identification of a novel kinase target in Myotonic Dystrophy type 1. UK Neuromuscular Translational Research Conference, Cambridge, 20th April 2018. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Scientific research talk
Year(s) Of Engagement Activity 2018
 
Description MDSG 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact The presentation to 200 patients and their families outlined research progress. I also ran 2 workshops on the same day, each attended by 30 - 50 people to provide further insight to research. The workshops lasted 1 hr and took the form of question and answer sessions.
Year(s) Of Engagement Activity 2016
 
Description MDSG AGM 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 200 attendees, mostly patients and families with myotonic dystrophy but also some healthcare professionals.

Positive feedback from those present
Year(s) Of Engagement Activity 2013
 
Description MDSG AGM Newcastle 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Around 200 patients, carers and other family members affected by myotonic dystrophy attended

Patients have volunteered to participate in a National Register and for clinical trials
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description MDSG Nottingham 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Questions and subsequent discussion

Patients wanted to participate in research
Year(s) Of Engagement Activity 2014
 
Description MDSG Nottingham 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Informing a patient group about research progress
Year(s) Of Engagement Activity 2015
 
Description MDUK Meeting London 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Workshop organized for muscular dystrophy patients
Year(s) Of Engagement Activity 2015
 
Description Myotonic Dystrophy Research Progress. Myotonic Dystrophy Support Group Annual Meeting, Oxford, 16th June 2018 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Presenter and participant in a day-long meeting of the DM support group
Year(s) Of Engagement Activity 2018
 
Description Myotonic Dystrophy and Congenital Heart Disease - A tale of two kinases. University of Newcastle 15th December 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Scientific talk to a University department followed by Q & A
Year(s) Of Engagement Activity 2017
 
Description Rare Diseases Day meeting with Myotonic Dystrophy Support Group, Carlton UK, 26th March 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Celebration of Rare Disease Day with talks and lunch
Year(s) Of Engagement Activity 2018
 
Description Rare Diseases Day meeting with Myotonic Dystrophy Support Group, Carlton UK, 4th March 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Regional meeting of the DM support group with presentation lunch and discussion
Year(s) Of Engagement Activity 2019
 
Description Research Progress in Myotonic Dystrophy. Muscular Dystrophy UK, Annual meeting, Cambridge, 21st April 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation to a patient support group
Year(s) Of Engagement Activity 2018
 
Description Research Progress in Myotonic Dystrophy. Myotonic Dystrophy Support Group Annual Meeting, Nottingham, 24th June 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation to patient support group with questions and discussion
Year(s) Of Engagement Activity 2017