Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.
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成年人类骨髓衍生，培养，合并，同种异体间质基质细胞（STEMPEUCEL®）的功效和安全性：膝关节骨关节炎中的临床前和临床试验。
DOI：
10.1186/s13075-016-1195-7
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发表时间：
2016-12-20
影响因子：
4.9
通讯作者：
Majumdar AS
中科院分区：
文献类型：
--
作者：
Gupta PK;Chullikana A;Rengasamy M;Shetty N;Pandey V;Agarwal V;Wagh SY;Vellotare PK;Damodaran D;Viswanathan P;Thej C;Balasubramanian S;Majumdar AS
骨关节炎（OA）是一种常见的、使人衰弱的慢性关节退行性疾病。目前，正在探索基于细胞的疗法来修复膝关节中受损的关节软骨。通过使细胞向软骨形成谱系分化并定量硫酸化糖胺聚糖（sGAG），测定成人骨髓来源的、培养的、合并的同种异体间充质基质细胞（Stempeucel®）的体外分化潜能。单碘乙酸（MIA）诱导的OA临床前模型已用于证明疼痛减轻和软骨形成。在临床研究中，60名OA患者随机接受不同剂量的细胞（25，50，75，150百万细胞）或安慰剂。通过关节内（IA）注射将Stempeucel®施用到膝关节中，然后施用2 ml透明质酸（20 mg）。在基线和随访1、3、6和12个月时进行主观评价-疼痛视觉模拟评分（VAS）、间歇性和持续性骨关节炎疼痛（ICOAP）、西安大略和麦克马斯特大学骨关节炎（WOMAC-OA）指数。在基线、6个月和12个月随访时对膝关节进行磁共振成像，以进行软骨评价。Stempeucel®在体外分化成软骨形成谱系，Sox 9基因下调，Col 2A基因上调。此外，Stempeucel®分化成软骨细胞并合成显著量的sGAG（30 ± 1.8 μg/μg GAG/DNA）。在OA的临床前模型中，Stempeucel®显著减轻了疼痛，并修复了大鼠受损的关节软骨。在临床研究中，Stempeucel®的IA给药是安全的，并且在2500万细胞剂量组中观察到所有主观参数（VAS、ICOAP和WOMAC-OA评分）的改善趋势，尽管与安慰剂相比，这在统计学上不显著。不良事件主要发生在较高剂量组（50、75和1.5亿个细胞）。膝关节疼痛和肿胀是最常见的不良事件。膝关节的全器官磁共振成像评分与基线和安慰剂组相比无任何差异。Stempeucel®关节内给药安全。2500万个细胞的剂量可能是测试中最有效的止痛剂量。需要在更大患者人群中开展临床研究，以证明Stempeucel®在OA中的稳健疗效。Clinicaltrials.gov NCT01453738。2011年10月13日注册。
Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint. The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel® was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations—visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index—were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation. Stempeucel® differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel® differentiated into chondrocytes and synthesized a significant amount of sGAG (30 ± 1.8 μg/μg GAG/DNA). In the preclinical model of OA, Stempeucel® reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel® was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group. Intra-articular administration of Stempeucel® is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel® in OA. Clinicaltrials.gov NCT01453738. Registered 13 October 2011.