Department of Health Funded Project: Progress Report, December 2004

Department of Health Funded Project:
“Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A UK Consortium for Preclinical Optimisation and a Phase I/II Clinical Trial Using Antisense Oligonucleotides”

Progress Report 1: December 2004

Contents:


Background on Project

Duchenne muscular dystrophy (DMD) arises from faults in the dystrophin gene, which result in the absence or near total absence of dystrophin protein. Without dystrophin the muscle cells weaken with time and eventually die.

There are currently no treatments that will prevent this breakdown of muscle cells. The aim of this project is to test, in a variety of different systems including humans, the potential of ‘molecular patches’ (antisense oligonucleotides), to reduce the severity of Duchenne and potentially increase quality and length of life. It is however not a cure and even if shown to be successful would require repeated administration.

Research in the laboratory in mice and cultured muscle cells has shown the potential of ‘molecular patches’ to bind to the faulty dystrophin code. During protein production, parts of the dystrophin gene code (including the fault) are removed (by a process called exon skipping), and normal parts of the code are joined together to form a shortened semi-functional dystrophin protein.

Demonstrating that such a technique works in the laboratory is an essential first step, however its true potential can only be evaluated in the affected individuals. The object of this project is to advance the research sufficiently to perform the first UK clinical safety trial.

The specific aims are:

  • to optimise the current formulations both in terms of the sequence of the ‘patch’ and the carrier molecule used to improve the delivery of the ‘patch’;
  • to develop a specialised mouse model so that therapeutic effects can be studied in a whole mouse at various times during treatment. It is important to know where the ‘patch’ is in the body and to quantify the amount of protein produced at different times after treatment;
  • to further develop a delivery system to target all affected muscle (systemic delivery);
  • to perform the first UK clinical phase I/II trial.

The project will run for four years.



Where are we now?

Contract
The announcement of £1.6 million of funding for this project came at the end of March 2004. Following this the Department of Health issued a Contract to the Muscular Dystrophy Campaign who is acting as the Contractor and will sub-contract the research to four Research Institutions; Imperial College, Royal Holloway, Newcastle University and Oxford University. It has taken some time to finalise these Contracts, the reasons being:

a) The initial contract required several amendments to allow the Muscular Dystrophy Campaign to effectively contract the research out to the Research Institutions and share the results of this research with the three charities involved.
b) Once the Contract between the Muscular Dystrophy Campaign and the Department of Health was finalised, the Muscular Dystrophy Campaign needed to draw up Contracts with the Research Institutions. It was important that these Contracts were standardised and agreed by all the Institutions. This has finally been achieved and amended Contracts have been sent to the Research Institutions for signing which is hopefully just a formality. The project is due to start in January 2005.

However, during these lengthy Contract negotiations, the Consortium have worked hard to progress the research and several important steps have already been taken. It is important to note that the delay in finalising contracts has not prevented progress and this time has effectively been used by the Consortium to develop ideas and collaborations and to iron out potential stumbling blocks. As the application was put together rapidly there were bound to be issues that required further thought and planning and this has been the focus of the Consortium over the past eight months.

Project progress

a) Meeting of the Scientific Board and the Consortium
In September, the Scientific Board met with the Consortium for the first time. The role of the Scientific Board is to evaluate and monitor the scientific progress of this project. The Board consists of experts from different areas of research relevant to the project and one representative from each of the three Charities – Parent Project UK, the Muscular Dystrophy Campaign and the Duchenne Family Support Group. The Board has unanimously agreed that the charity representatives should not have voting rights due to potential conflicts of interest, but their opinions and comments are highly valued.

At this meeting each member of the Consortium presented their section of the project and this was then discussed in length to ensure all members were clear as to their role in this research. In addition, the Consortium presented milestones, which will be evaluated continuously by the Board to ensure the research is progressing optimally.

Some of the early milestones include: 

  • Obtaining clear guidance/advise on what will be required for toxicity testing for the antisense oligonucleotide and the carrier molecule;
  • Selection of the antisense oligonucleotide chemistry for intramuscular injection;
  • Selection of the best carrier molecule to be used in the clinical trial;
  • Obtaining ethical approval for the relevant sections of the necessary preliminary research. Final ethical approval for the safety trial can only be sought after final decisions have been made on the chemistry of the antisense oligonucleotides, the carrier to be used and the muscle that will be targeted.

The Consortium members meet regularly and it was agreed that the Scientific Board should meet together with the Consortium again in six months time to evaluate progress.

b) European Neuromuscular Centre meeting
As many members are aware, this research is not limited to the UK and the Dutch team, headed by Professor Gertjan van Ommen, is planning a similar trial in the Netherlands. Professors’ Francesco Muntoni, Kate Bushby and Gertjan van Ommen set up a meeting at the European Neuromuscular Centre at the end of October to bring together the groups working in this area, including Dr Steve Wilton from Australia.

This was a highly successful meeting which has resulted in extensive discussions over the planned trials and a consensus to collaborate together to ensure there is no unnecessary duplication of research and that the results from these two trials can be compared and evaluated to maximise the information obtained. A summary of this meeting is available on the European Neuromuscular Centre website at the following address: www.enmc.org and a full report will be published shortly in the journal Neuromuscular Disorders.

It was also agreed at this meeting to establish an International Consortium on Antisense Oligonucleotides in Duchenne Muscular Dystrophy. Another important area discussed was that information should be readily available both to explain the research and to update the progress being made. The European Neuromuscular Centre have agreed to set up a place on their website for this information and materials are currently being developed.

c) Meeting with the Medicines and Healthcare products Regulatory Authority (MHRA)
In December, members of the Consortium met with the MHRA for the first time to discuss the exact requirements for toxicity testing of the antisense oligonucleotide and carrier to be used in the clinical trial.

This was an extremely valuable meeting, expert guidance was given and Consortium members now have a much clearer idea of what is expected for the first safety trial.

Again as mentioned previously, the unusually tight deadline for submission of this application meant that it was not possible to accurately forecast the exact costs that would be incurred. Toxicity testing is one such example, before one has received guidance as to what will be required, it is impossible to accurately cost. It is now clear however, that what was budgeted for toxicity testing is not sufficient and additional funding will be needed. It is likely that other areas such as the costs of the regulatory approval process etc may also be under-estimated. This does not mean that the project cannot take place, but rather that the three charities may be called upon again to lobby for additional funding should appropriate opportunities present themselves.



Future Projects

It is important to realise that this research is just one of many steps that will be required to develop a therapy for Duchenne muscular dystrophy. If this research and the initial safety trial are successful we need to follow this with further trials, ideally using a systemic delivery system to target all affected muscle. Whilst there is some money for the development of systemic delivery within the Department of Health application, this does not even begin to cover the expenses that will be required for further trial development.

Representatives from the three charities meet regularly to discuss developments, lobbying opportunities and future projects. Both the charities and the Consortium agree that it is essential to begin to develop a systemic delivery project now so that by the time we have completed the initial safety trial using intramuscular injection, we are ready to move towards a systemic delivery trial using ‘molecular patches’. In the new year a concerted effort will be made to develop this new project.

The Department of Health requires quarterly progress reports. Lay summaries of these will be written to let members know of developments in the Project.

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