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

用于肌肉再生的成肌细胞递送产品的临床前评估

• 批准号: MR/R014108/1
• 负责人: Richard Day
• 金额: $ 32.11万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR014108%2F1
• 关键词: Pre; Clinical; Evaluation; Myoblast; Delivery

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.

胰岛素是一个重要的未满足的临床需求。在英国，粪便失禁（FI）估计影响约2%的成年人，尿失禁约24%。这些数字增加到超过一半的养老院居民。据估计，失禁的综合成本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很有前途的解决方案，以恢复括约肌的功能，提供再生。早期的临床研究调查了患者自身肌肉前体细胞悬浮液的递送，报告了混合的结果，一些研究显示肌肉功能没有改善。这可能是由于细胞在次优条件下被递送，这是由于它们在体外被操纵并且作为悬浮液递送，这是肌肉细胞的非自然状态。为了解决这个问题，我们开发了新型多孔微粒，肌肉前体细胞容易附着并以更健康的方式生长。我们的长期目标是使用这些微粒作为一种新型再生医学的一部分，以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，然后将它们仍然固定在微粒上，进入有缺陷的括约肌。随着前体细胞与肌肉整合，微粒慢慢降解，形成新的功能组织，恢复肌肉功能。在我们这样做之前，我们需要清楚地证明与传统的递送方法相比，递送附着在微粒上的细胞的有益效果。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其形成新肌肉的潜力来解决这一问题。然后，我们将研究微粒子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方案将用于弥合翻译差距，并证明该技术的发展需要更广泛的临床前测试，然后我们才能开始将该产品作为一种新型的人类再生医学进行临床测试，以恢复骨骼肌。虽然失禁是当前项目中创新疗法的临床目标，但正在解决的转化差距将为其他条件提供平台技术，其中有效的细胞递送可能具有治疗价值。这包括诸如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、神经系统疾病、骨重建和慢性伤口愈合等病症。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，经济和心理效益。

项目成果

Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering.

• DOI: 10.1016/j.celrep.2018.03.091
• 发表时间: 2018-04-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Maffioletti SM;Sarcar S;Henderson ABH;Mannhardt I;Pinton L;Moyle LA;Steele-Stallard H;Cappellari O;Wells KE;Ferrari G;Mitchell JS;Tyzack GE;Kotiadis VN;Khedr M;Ragazzi M;Wang W;Duchen MR;Patani R;Zammit PS;Wells DJ;Eschenhagen T;Tedesco FS
• 通讯作者: Tedesco FS

Promotion of Proangiogenic Secretome from Mesenchymal Stromal Cells via Hierarchically Structured Biodegradable Microcarriers.

• DOI: 10.1002/adbi.202000062
• 发表时间: 2020-07
• 期刊: Advanced biosystems
• 影响因子: 4.1
• 作者: Simitzi C;Hendow E;Li Z;Day RM
• 通讯作者: Day RM