Gupta Pawan Kumar, Chullikana Anoop, Rengasamy Mathiyazhagan, Shetty Naresh, Pandey Vivek, Agarwal Vikas, Wagh Shrikant Yeshwant, Vellotare Prasanth Kulapurathu, Damodaran Devi, Viswanathan Pachaiyappan, Thej Charan, Balasubramanian Sudha, Majumdar Anish Sen
Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
M.S Ramaiah Medical College & Hospitals, MSR Nagar, MSRIT Post, Bangalore, 560054, India.
Arthritis Res Ther. 2016 Dec 20;18(1):301. doi: 10.1186/s13075-016-1195-7.
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.
骨关节炎（OA）是一种常见的、使人衰弱的关节慢性退行性疾病。目前，正在探索基于细胞的疗法来解决膝关节受损关节软骨的修复问题。
通过将成人骨髓来源的、培养的、汇集的同种异体间充质基质细胞（Stempeucel®）向软骨生成谱系分化并定量硫酸化糖胺聚糖（sGAG），来确定其体外分化潜能。单碘乙酸（MIA）诱导的骨关节炎临床前模型已被用于证明疼痛减轻和软骨形成。在临床研究中，60例骨关节炎患者被随机分配接受不同剂量的细胞（2500万、5000万、7500万或1.5亿个细胞）或安慰剂。通过关节内（IA）注射将Stempeucel®注入膝关节，随后注射2 ml透明质酸（20 mg）。在基线以及随访的1、3、6和12个月时进行主观评估——疼痛视觉模拟量表（VAS）、间歇性和持续性骨关节炎疼痛（ICOAP）以及西安大略和麦克马斯特大学骨关节炎（WOMAC-OA）指数。在基线以及随访的6和12个月时对膝关节进行磁共振成像以评估软骨。
Stempeucel®在体外向软骨生成谱系分化，Sox9基因下调，Col2A基因上调。此外，Stempeucel®分化为软骨细胞并合成了大量的sGAG（30±1.8μg/μg GAG/DNA）。在骨关节炎临床前模型中，Stempeucel®显著减轻疼痛，并修复了大鼠受损的关节软骨。在临床研究中，关节内注射Stempeucel®是安全的，在2500万个细胞剂量组的所有主观参数（VAS、ICOAP和WOMAC-OA评分）中都有改善趋势，尽管与安慰剂相比无统计学意义。不良事件在较高剂量组（5000万、7500万和1.5亿个细胞）中占主导。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没有差异。
关节内注射Stempeucel®是安全的。在测试的用于减轻疼痛的剂量中，2500万个细胞的剂量可能是最有效的。需要更大患者群体的临床研究来证明Stempeucel®在骨关节炎中的强大治疗效果。
Clinicaltrials.gov NCT01453738。于2011年10月13日注册。
