Pre-Clinical Evaluation of a Myoblast Delivery Product for Muscle Regeneration

大小便失禁是一种重要的未得到满足的临床需求。在英国，据估计，大便失禁(FI)影响了大约2%的成年人，而尿失禁大约影响了24%。这些数字增加到疗养院居民的一半以上。据估计，大小便失禁的总成本每年要花费英国医疗系统数十亿英镑。细胞疗法为恢复提供可控性的括约肌功能提供了一个有希望的解决方案。调查患者自身肌肉前体细胞悬浮液交付的早期临床研究报告了好坏参半的结果，一些研究表明肌肉功能没有改善。这可能是由于细胞处于次优状态，因为它们在体外进行操作，并以悬浮液的形式提供，这对肌肉细胞来说是一种不自然的状态。为了解决这个问题，我们开发了新型的多孔微粒，肌肉前体细胞很容易附着在上面，并以更健康的方式生长。我们的长期目标是利用这些微粒作为一种新型再生药物的一部分，培养患者自己的肌肉细胞，这些细胞是从腿部肌肉的小活检中获得的，然后将它们输送到有缺陷的括约肌中，这些细胞仍然固定在微粒上。随着前体细胞与肌肉结合，微粒慢慢降解，形成新的功能组织，恢复大小便。在我们能够做到这一点之前，我们需要清楚地展示与传统的递送方法相比，递送附着在微粒上的细胞的益处。该项目将首先通过研究附着在微粒上的肌肉前体细胞是否保持形成新肌肉的潜力来解决这个问题。然后，我们将研究微粒保留植入部位的肌肉前体细胞并形成新肌肉的能力。该项目产生的数据和方案将用于弥合翻译差距，并证明该技术的进步到更广泛的临床前测试所需的，然后我们才能开始将该产品作为一种新型再生药物在人类身上进行临床测试，以恢复可控性。虽然大小便失禁是当前项目中创新疗法的目标临床条件，但正在解决的翻译差距将为其他条件提供平台技术，在这些条件下，高效的细胞输送可能具有治疗价值。这包括导致肌肉功能不全的局部形式的肌肉营养不良或肌肉创伤，以及心力衰竭、神经疾病、骨骼重建和慢性伤口愈合等情况。如果成功，该治疗系统将为英国NHS带来巨大的经济效益，并为患者带来社会、经济和心理上的好处。

Incontinence is a significant unmet clinical need. In the UK, faecal incontinence (FI) is estimated to affect approximately 2% of adults and urinary incontinence approximately 24%. These figures increase to over half of nursing home residents. The combined cost of incontinence is estimated to cost the UK healthcare system £billions per year. Cell therapy offers a promising solution to restoring the function of sphincter muscles that provide continence. Early clinical studies investigating delivery of a suspension of patients' own muscle precursor cells have reported mixed results, with some studies showing no improvement in muscle function. This is possibly due to the cells being delivered in a sub-optimal condition due to their manipulation outside the body and delivery as a suspension, an unnatural state for a muscle cell. To address this, we have developed novel porous microparticles that muscle precursor cells readily attach to and grow in a healthier manner. Our long-term aim is to use these microparticles as part of a novel regenerative medicine to grow patients' own muscle cells, obtained from a small biopsy from a leg muscle, before delivering them, still anchored to microparticles, into the defective sphincter muscle. The microparticles slowly degrade as the precursor cells integrate with the muscle, forming new functional tissue that will restore continence. Before we can do this, we need to clearly demonstrate the beneficial effects of delivering cells attached to the microparticles compared with conventional delivery methods. The project will address this firstly by investigating whether the muscle precursor cells attached to the microparticles retain their potential to form new muscle. We will then investigate the ability of the microparticles to retain the muscle precursor cells at the site of implantation and form new muscle.The data and protocols generated from the project will be used to bridge the translational gap and justify progression of the technology to more extensive pre-clinical testing required before we can start clinical testing of the product as a new type of regenerative medicine in humans to restore continence. Although incontinence is the clinical condition targeted with the innovative therapy in the current project, the translational gap being addressed will offer a platform technology for other conditions where efficient delivery of cells is likely to be of therapeutic value. This includes conditions such as localized forms of muscular dystrophy or muscle trauma that result in muscle insufficiency, as well as heart failure, neurological disease, bone reconstruction, and healing of chronic wounds. If successful, the therapeutic system will have tremendous economic benefits to the UK NHS, as well as delivering social, economic and psychological benefits to patients.