Advanced peptide-oligonucleotide therapy for Myotonic Dystrophy Type 1

点击翻译按钮获取中文摘要

Myotonic dystrophy type 1 (DM1) is a multisystem disease and the most common adult form of muscular dystrophy, leading to severe, progressive muscle wasting and weakness, but which also impacts the eye, heart and brain. It can also affect infants and results in severe disability and significantly shortened life span. No treatment is presently available. The disease is caused by a genetic defect in the DMPK gene, which when mutated results in the formation of a toxic product that directly leads to disease. We have developed a novel method based on short synthetic DNA drugs (known as antisense oligonucleotides) which bind to and inactivate the mutated gene product, and which we attach to potent protein fragments or peptides which allows the DNA drug to be delivered with very high efficiency to ALL of the affected tissues including muscle, heart and brain. We have already demonstrated the proof that this approach can work both in cell cultures and also in DM1 animal models. However, there is still room for improvement in the delivery of the treatment to muscle (especially diaphragm) and heart which is especially critical since the life span of DM1 patients is reduced particularly due to respiratory insufficiency and cardiac failure. Here we now plan to capitalise on our peptide technology to select and optimise the best delivery peptide which would permit highly effective delivery of the DNA drug to all affected tissues in the absence of unwanted side effects. Our laboratories are world-leading and have all necessary skills to deliver the project plan. The major objective of this proposal is to develop this peptide-DNA method into a drug that could be used in patients. More specifically the objectives are to (1) screen a number of peptide-DNA compounds for their ability to treat the main features of the disease in human cells; (2) optimise lead and back-up compounds selected for high efficiency activity in the tissues most affected in a DM1 mouse model, in the absence of unwanted side effects; (3) establish the doses at which the treatment is most effective and how long the effects last.This is a highly innovative project that meets an unmet clinical need and could have a very high clinical impact but we first need to optimize the delivery of the treatment to the tissues most affected by DM1 (heart and diaphragm) and that represent the major limiting factor for DM1 patient survival, before we start clinical development of the compounds for evaluation in patients. To date the only treatments for DM1 target some of the symptoms such as the removal of cataracts or hormonal replacement therapy but there are no treatments that directly target the cause of the disease. Therefore, the optimization of these peptide-DNA compounds able to block the product of the mutated gene is a high priority for preclinical and clinical development. Additionally, an anticipated output of this project is intellectual property involving the most successful compounds. Moreover, the improvement of compound delivery into muscles would be a major step in the development of an effective therapy not only for DM1 but potentially for other muscular dystrophies.