End of project summary
Changes in the DMPK gene can cause problems for cells, causing myotonic dystrophy type 1 (DM1).
As part of this project, Professor Matthew Wood and colleagues developed molecular patches that can block the toxic effects of changed DMPK . This is important because the changed RNA accumulates in the nucleus, which can be deadly for the cells and can ultimately cause DM1. The team assessed the efficiency and safety of these molecular patches. The most promising molecular patch was selected for the final stage of preclinical studies.
This molecular patch can reverse the weakening caused by DM1 in cells originating from people with DM1, and in mouse models of DM1. This resulted in resumed correct contraction and relaxation of the muscles.
Professor Wood and colleagues also found a way to get the patch into the heart and diaphragm (the muscle that helps us breathe), by coupling them to short pieces of proteins called peptides. These peptides act like a ‘password’ to let the molecular patch into the right cells.
Finally, the researchers have established the doses at which the patch is most efficient, as well as the best way to administer it to people with the condition, bringing us a step closer to clinical trials.
What are the aims of the project?
Myotonic dystrophy type 1 is caused by an expansion of DNA within the DMPK gene. This leads to the production of mutant DMPK RNA, which gets trapped in the nucleus and has toxic effects to the cell.
The aim of this project is to develop an advanced molecular patch that binds to the mutant DMPK RNA and blocks its toxic effects. This could therefore be a potential treatment for people with myotonic dystrophy type 1.
Professor Wood and his team will link the molecular patches to short fragments of protein called peptides. These peptides help the molecular patches to get inside cells, thus improving their delivery into muscles and other parts of the body.
Firstly, the researchers will test several peptide-linked molecular patches in cells originating from people with myotonic dystrophy type 1 and mouse models. They will then select the best molecular patch, based on the ability to reduce symptoms with minimal side effects. Finally, they will inject different doses of the lead molecular patch into mouse models and then monitor its effects in the long-term. This will establish the doses at which the patch is most effective and how long the effect lasts.
Why is this research important?
Problems in the heart and diaphragm can be life-limiting for people with myotonic dystrophy type 1, so it is crucial that future treatments target these organs. Molecular patches that are currently in clinical trial are not very good at getting inside the heart and diaphragm. This project will help to address this problem by linking the molecular patches to peptides. Enhancing the technology in this way could therefore lead to better therapeutic outcomes.
How will the outcomes of this research benefit people with myotonic dystrophy?
To date, the only treatments available for people with myotonic dystrophy type 1 are those that address some of the symptoms. This research could lead to the development of a treatment that directly targets the genetic cause of the condition. This may have the potential to reverse, or at least slow down, the deterioration of tissues affected by the condition, including the movement muscles, heart, diaphragm and brain.
How might this research impact on other neuromuscular conditions?
Molecular patches have the potential to treat the underlying genetic causes of a range of muscle-wasting conditions. This project will enhance molecular patch technology so that it can target muscles effectively and efficiently, which will be helpful for designing molecular patches for other neuromuscular conditions.
Grant information
Project leader: Professor Matthew Wood
Institute: Oxford University
Condition: Myotonic dystrophy type 1
Duration: three years, starting 2016
Total cost: £219,992
Official title: Advanced peptide-oligonucleotide therapy for myotonic dystrophy type 1
Further information
Read an update on this project here (25/10/2019)
Find out what other myotonic dystrophy research projects we’re funding
Read our factsheet on myotonic dystrophy
Find out more about the MDUK Oxford Neuromuscular Centre
This research would not have been possible without individual donations, family fundraising activities, trusts and corporate support for our Myotonic Research Breakthrough Fund.
Donate now and help us ensure that effective treatments and expert care are available to all those living with myotonic dystrophy. Thank you.