Chondrocytes from Clinical Grade Embryonic Stem Cells

骨关节炎是一种关节衰弱性疾病，影响25%的65岁以上成年人（世卫组织估计）。它会导致疼痛、残疾和丧失独立性，从而导致生活质量低下。在欧盟，它的疾病负担排名第12位，有3500万至4000万患者，随着人口老龄化的加剧，这一数字将会上升。目前的临床治疗仅限于缓解疼痛，无法延缓或逆转病情。不可逆转的损伤关节最终会被合成假体取代，这在老年患者中是成功的（bbb65），但在年轻患者中不太成功，因为他们的预期寿命比假体大得多，翻修手术不太成功。因此，改善OA治疗的临床需求尚未得到满足。目前的策略包括软骨修复（ACI），使用患者自己的软骨细胞，从完整的组织区域采集。然而，ACI的结果并不比非细胞矫形治疗好，它需要2次手术和损伤其他完整的组织。患者的骨髓干细胞也在测试中，但这也需要两次手术和患者特异性细胞培养。为了克服患者自身细胞质量不稳定和需要两次手术的问题，我们开发了一种从人胚胎干细胞（hESCs）中生成软骨细胞的方案。该方案完全不含血清，化学定义，产生高达97%的软骨细胞。我们现在需要调整这一过程，以输送适合临床应用的细胞。这需要使用完全经过验证的临床级试剂，扩大规模以产生更多的细胞，以及储存和运送细胞到临床的方法。我们将用曼彻斯特和英国其他中心衍生的新一代高质量（临床级）干细胞系来验证该方案。使用hESCs的优势在于，它们可以扩增产生足够的软骨细胞来治疗大量患者，这使得这种疗法在NHS上具有成本效益。后续的体内试验将对细胞系在修复大鼠膝关节局灶性缺陷方面的成功程度进行分级（已经在研究级细胞中得到证实），从而使我们能够评估体内软骨修复的质量，并评估任何肿瘤形成的发生率或其他不良反应。该计划将显示hESC衍生的软骨细胞是否能够产生、输送并能够完成透明软骨的修复。该奖项将使我们能够建立针对局灶性软骨缺损患者进行一期临床试验的手段和方法。

Osteoarthritis is a debilitating condition of joints affecting 25% of adults over 65 yrs (WHO estimate). It causes pain, disability and loss of independence, which results in a poor quality of life. In the EU it is ranked 12th for disease burden with 35-40 million sufferers and this is set to rise with increased ageing of the population. Current clinical treatment is limited to pain relief with nothing able to delay or reverse the condition. Irreversibly damaged joints are eventually replaced by synthetic prostheses, which are successful in older patients (>65), but less so in younger patients whose life expectancy is much greater than that of the prosthesis and revision surgery is less successful. There is therefore a large unmet clinical need for improved treatment for OA. Current strategies include cartilage repair (ACI) using the patient's own chondrocytes, harvested from intact areas of tissue. However, the outcome of ACI is little better than non-cellular orthopaedic treatments and it requires 2 operations and damage to otherwise intact tissue. Patients' stem cells are also being tested from bone marrow, but this also requires 2 operations and patient specific cell culture. To overcome the problem of the variable quality of the patients' own cells and the need for 2 operations, we have developed a protocol to generate chondrocytes from human embryonic stem cells (hESCs). The protocol is entirely serum free, chemically defined and yields up to 97% chondrogenic cells. We now need to adapt this procedure to deliver cells suitable for clinical applications. This requires the use of entirely validated clinical grade reagents, scale up to generate larger numbers of cells and methods to store and deliver cells to the clinic. We will validate this protocol with a new generation of very high quality (clinical grade) stem cell lines derived in Manchester and by other Centres across the UK. The advantage of using hESCs is that they can be expanded to produce enough chondrogenic cells to treat large numbers of patients, making such a therapy cost-effective on the NHS. Follow-up tests in vivo will grade lines for success in repairing focal defects in rat knee joints (already shown for research grade cells) to allow us to assess the quality of in vivo cartilage repair and assess any incidence of tumour formation, or other adverse effects. The plan will show if hESC derived chondrocytes can be produced, delivered and are able to complete hyaline cartilage repair. This award will allow us to establish the means and methods to move forward towards phase 1 clinical trials for patients with focal cartilage defects.