Cell mediated gene therapy for Duchenne muscular dystrophy: trans-correction of resident nuclei to amplify dystrophin expression

该研究项目旨在优化最近在杜氏肌营养不良症患者中测试的一种治疗方法，并将其扩展到其他罕见的肌肉遗传疾病，以便将来一种策略可以适用于更多的疾病。肌肉萎缩症是由单个基因突变引起的，导致人体肌肉功能受损和死亡。这反过来又导致不同程度的残疾，在最坏的情况下，是毁灭性的；它们会降低生活质量，导致过早死亡。虽然个别的肌肉萎缩症很罕见或极其罕见，但它们共同影响着成千上万的人，对负责提供姑息疗法和医疗援助的国家卫生服务部门构成了重大挑战，这种挑战往往持续数十年。为了“治愈”遗传疾病，有必要替换或修复有缺陷的基因，这可以通过使用病毒载体（在实验室中经过修饰以将正确版本的基因传递到细胞中的病毒）或干细胞（可用于在体内产生任何其他类型细胞的细胞）来实现。为了确保它们被身体接受，干细胞可以在实验室“修复”后从相关供体（例如兄弟姐妹）或患者自己身上获得。到目前为止，这些疗法已经成功地治疗了几种影响血液、皮肤和角膜的遗传疾病。这是可能的，因为移除病变组织并替换它相对容易。这种方法不可能用于影响心脏、肝脏或大脑的疾病。在这些情况下，健康细胞将不得不纠正遗传缺陷，并以某种方式帮助驻留的患病细胞的功能。我们治疗的创新之处在于，注射到患者动脉中的干细胞最终会均匀地分布在全身。其中一些干细胞可以穿过血管，进入身体周围的组织并最终修复它。然而，这一过程还不够有效，无法显著改善患者的病情。为了实现这一目标，我们正在详细研究移植过程的每一步。在这个特定的项目中，我们正在开发一种策略，通过这种策略，单个基因校正的细胞也可以校正新再生的肌肉纤维中由许多细胞核组成的邻近细胞核。这将扩大治疗效果。研究方案的成功完成将迅速导致一项新的临床试验，然后可能扩展到更罕见的肌肉遗传疾病，增加对患者的益处。

This research projects aims at optimising a treatment that was recently tested in patients affected by Duchenne muscular dystrophy, with the idea to extend it to other rare genetic diseases of the muscle, so that one strategy may in the future be adapted for more diseases. Muscular dystrophies are caused by mutations in a single gene that leads to the impaired function and death of muscles in the human body. This in turn causes disability of variable severity that, in the worse cases, are devastating; they compromise quality of life and lead to a premature death. Although individual muscular dystrophies are rare or extremely rare, together they affect many thousands of people and represent a major challenge for National Health Services, in charge of providing palliative therapies and medical assistance, often over decades. In order to "cure" genetic diseases it is necessary to replace or repair the defective gene and this can be achieved by using viral vectors (viruses that have been modified in the laboratory to deliver a correct version of the gene into cells) or stem cells (cells which can be used to generate any other type of cell in the body). To make sure they're accepted by the body, stem cells can be derived from a related donor (e.g. a sibling) or from the patient themselves, after having been "repaired" in the lab. These therapies have been successful so far for several genetic diseases affecting the blood, the skin, and the cornea. This has been possible because it is relatively easy to remove the diseased tissue and replace it. This approach is not possible for diseases affecting the heart, the liver or the brain. In these cases, healthy cells will have to correct the genetic defect and somehow help the function of the resident diseased cells.The innovative aspect of our treatment is based on the fact that stem cells which are injected into the arteries of patients end up distributed uniformly throughout the body. Some of these stem cells can then cross out of the blood vessel, move into the surrounding tissue of the body and eventually repair it. However, the process is not yet efficient enough to result in a noticeable improvement in patients. In order to achieve this, we are studying in detail each step of the transplantation procedure. In this specific project, we are developing a strategy by which, a single, genetically corrected cell will also correct neighbouring nuclei inside a newly regenerated muscle fibre that is composed of very many nuclei. This will amplify the therapeutic effect. The successful completion of the research programme will rapidly lead to a new clinical trial, that may be then extended to more rare genetic diseases of muscle, increasing the benefit for patients.