Advanced peptide-oligonucleotide therapy for Myotonic Dystrophy Type 1

强直性肌营养不良1型（DM 1）是一种多系统疾病和最常见的成人形式的肌营养不良症，导致严重的，进行性肌肉萎缩和无力，但也影响眼睛，心脏和大脑。它也会影响婴儿，导致严重残疾和寿命显著缩短。目前尚无治疗方法。这种疾病是由DMPK基因的遗传缺陷引起的，当突变时，会导致形成直接导致疾病的有毒产物。我们已经开发了一种基于短合成DNA药物（称为反义寡核苷酸）的新方法，其结合并修饰突变的基因产物，并且我们将其连接到有效的蛋白质片段或肽，这使得DNA药物能够以非常高的效率递送到所有受影响的组织，包括肌肉，心脏和大脑。我们已经证明了这种方法可以在细胞培养和DM 1动物模型中工作。然而，在向肌肉（特别是隔膜）和心脏递送治疗方面仍有改进的空间，这是特别关键的，因为DM 1患者的寿命特别是由于呼吸功能不全和心力衰竭而缩短。在这里，我们现在计划利用我们的肽技术来选择和优化最佳的递送肽，这将允许在没有不必要的副作用的情况下将DNA药物高效地递送到所有受影响的组织。我们的实验室是世界领先的，并拥有所有必要的技能，以提供项目计划。该提案的主要目标是将这种肽-DNA方法开发成可用于患者的药物。更具体地说，目标是（1）筛选许多肽-DNA化合物，以确定它们治疗人类细胞疾病主要特征的能力;（2）优化选择的先导和备用化合物，以在DM 1小鼠模型中受影响最严重的组织中发挥高效活性，且没有不必要的副作用;（三）这是一个高度创新的项目，可以满足尚未满足的临床需求，并可能产生非常高的临床影响，但我们首先需要优化治疗方法，在我们开始临床开发用于患者评估的化合物之前，我们需要对受DM 1影响最大的组织（心脏和膈肌）进行研究，这些组织代表了DM 1患者生存的主要限制因素。迄今为止，DM 1的唯一治疗方法是针对一些症状，如白内障或激素替代疗法，但没有直接针对疾病原因的治疗方法。因此，优化这些能够阻断突变基因产物的肽-DNA化合物是临床前和临床开发的高度优先事项。此外，该项目的预期产出是涉及最成功化合物的知识产权。此外，改善化合物递送到肌肉中将是开发有效疗法的重要一步，不仅用于DM 1，而且可能用于其他肌营养不良症。

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.