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

尿失禁是一个重要的未满足的临床需求。在英国，大便失禁（FI）估计影响约2%的成年人，尿失禁约24%。这些数字增加到养老院居民的一半以上。据估计，尿失禁的综合费用每年花费英国医疗保健系统数十亿英镑。细胞疗法提供了一个有希望的解决方案，以恢复括约肌的功能，提供节制。早期临床研究对患者自身肌肉前体细胞悬浮液的递送进行了研究，结果好坏参半，一些研究显示肌肉功能没有改善。这可能是由于细胞在体外被操纵并以悬浮液的形式递送，这是肌肉细胞的一种不自然状态，因此在次优状态下递送。为了解决这个问题，我们开发了一种新的多孔微颗粒，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医学的一部分来培养患者自己的肌肉细胞，这些细胞是从腿部肌肉的一小块活组织切片中获得的，然后再将它们固定在微粒上，植入有缺陷的括约肌。当前体细胞与肌肉结合时，微粒会慢慢降解，形成新的功能组织，恢复失禁。在我们能够做到这一点之前，我们需要清楚地证明与传统的递送方法相比，将细胞附着在微粒上的递送方法的有益效果。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留形成新肌肉的潜力来解决这个问题。然后，我们将研究微颗粒在植入部位保留肌肉前体细胞并形成新肌肉的能力。该项目产生的数据和协议将用于弥补翻译方面的差距，并证明该技术的进展需要进行更广泛的临床前测试，然后我们才能开始对该产品进行临床测试，将其作为一种新型的再生药物用于人类，以恢复失禁。尽管在当前项目中，创新疗法针对的是尿失禁的临床状况，但正在解决的转化差距将为其他状况提供一个平台技术，在这些情况下，有效的细胞递送可能具有治疗价值。这包括局部形式的肌肉萎缩或肌肉创伤，导致肌肉功能不全，以及心力衰竭、神经系统疾病、骨骼重建和慢性伤口愈合。如果成功，该治疗系统将为英国国民医疗服务体系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.