Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study.
Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study.
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DOI：
10.1016/j.ebiom.2016.09.011
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发表时间：
2016-10
期刊：
影响因子：
11.1
通讯作者：
Segal, Karen R.
中科院分区：
文献类型：
--
作者：
Packham, David K.;Fraser, Ian R.;Kerr, Peter G.;Segal, Karen R.
糖尿病肾病是最常见的终末期肾衰竭的原因。我们评估了成人同种异体骨髓来源的间充质前体细胞（MPC）在中重度糖尿病肾病患者中的安全性、耐受性和治疗效果。评估同种异体MPC单次静脉（IV）输注的多中心、随机、双盲、剂量递增、序贯、安慰剂对照试验（美国采用的名称：Rexlemestrocel-L）150 × 106（n = 10），300 × 106（n = 10）或安慰剂（n = 10）治疗估计肾小球滤过率（eGFR）20 - 50 ml/min/1.73 m2的糖尿病肾病成人。2013年7月至2014年6月期间，澳大利亚三家中心的30例患者入组，并以2：1的比例随机分为两个连续剂量队列，接受rexlemestrocel-L或安慰剂治疗。研究持续时间为60周。主要终点是安全性和耐受性。主要探索性疗效终点是eGFR和输注后12周通过99 Tc-DTPA血浆清除率（mGFR）直接测量的GFR较基线的变化。试验在www.example.com上注册（NCT 01843387）。所有患者均完成了研究，并被纳入意向治疗人群的分析中。没有与输注相关的急性不良事件（AE），也没有研究者认为与治疗相关的治疗相关AE或严重AE。没有患者发生持续的供体特异性抗HLA抗体。与安慰剂相比，单次IV输注Rexlemestrocel-L在第12周显示稳定或改善eGFR和mGFR的趋势。对于150 × 106和300 × 106细胞组，Rexlemestrocel-L组第12周时eGFR较基线变化与安慰剂相比的校正最小二乘均值（LSM ± SE）差异分别为4.4 ± 2.16和1.6 ± 2.15 ml/min/1.73 m2，mGFR分别为4.1 ± 2.75和3.9 ± 2.75。本研究证明了Rexlemestrocel-L在糖尿病肾病中的安全性，对肾功能的提示作用有待于更大规模、适当把握度的试验证实。我们报告了成人骨髓来源的同种异体间充质前体细胞（MPCs）在糖尿病肾病患者中的首次临床试验。我们的研究结果表明，在患有2型糖尿病和中度至重度肾损害的成人中，单次输注MPC是安全的。重要的是，我们没有观察到单次输注后对细胞疗法致敏的免疫学证据。需要进行更大规模、持续时间更长的研究，以确认对肾功能的疗效信号，如通过肾小球滤过率评估。这些研究对糖尿病肾病的新治疗选择有意义。目前糖尿病肾病的治疗仅将进展为肾衰竭的几率降低了16 - 25%。多项临床前研究表明，静脉注射间充质谱系细胞可以保护或改善肾功能和组织学。我们报告了成人同种异体骨髓来源的间充质前体细胞（MPCs）在成人2型糖尿病肾病患者中的首次试验。我们的研究结果证明了单次输注MPC的安全性。重要的是，在单次输注后没有对细胞疗法致敏的免疫学证据。需要更大规模、更长时间的研究来确认对肾功能有效性的潜在信号。对这种细胞疗法的进一步研究对保护肾功能的新治疗选择有意义。
Diabetic nephropathy is the most common cause of end stage renal failure. We assessed the safety, tolerability, and explored therapeutic effects of adult allogeneic bone-marrow derived mesenchymal precursor cells (MPC) in patients with moderate to severe diabetic nephropathy. Multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled trial assessing a single intravenous (IV) infusion of allogeneic MPC (United States adopted name: rexlemestrocel-L) 150 × 106 (n = 10), 300 × 106 (n = 10) or placebo (n = 10) in adults with diabetic nephropathy with an estimated glomerular filtration rate (eGFR) 20–50 ml/min/1.73 m2. Thirty patients at three Australian centers were enrolled between July 2013 and June 2014 and randomized 2:1, in two sequential dose cohorts, to receive rexlemestrocel-L or placebo. Study duration was 60 weeks. Primary endpoint was safety and tolerability. Primary exploratory efficacy endpoint was change from baseline in eGFR and directly measured GFR by 99Tc-DTPA plasma clearance (mGFR) at 12 weeks post-infusion. The trial was registered on ClinicalTrials.gov (NCT01843387). All patients completed the study and were included in analyses applied to the intention to treat population. There were no acute adverse events (AEs) associated with infusion and no treatment-related AEs or serious AEs were deemed treatment-related by investigators. No patients developed persistent donor specific anti-HLA antibodies. Relative to placebo, a single IV rexlemestrocel-L infusion showed trends of stabilizing or improving eGFR and mGFR at week 12. The adjusted least squares mean (LSM ± SE) differences from placebo in changes from baseline at 12 weeks in the rexlemestrocel-L groups were 4.4 ± 2.16 and 1.6 ± 2.15 ml/min/1.73 m2 for eGFR and 4.1 ± 2.75 and 3.9 ± 2.75 for mGFR for the 150 × 106 and 300 × 106 cell groups, respectively. This study demonstrates the safety of rexlemestrocel-L in diabetic nephropathy with suggestive effects on renal function to be confirmed in larger, appropriately powered trials. We report the first clinical trial of adult, bone-marrow derived allogeneic mesenchymal precursor cells (MPCs) in diabetic nephropathy patients. Our findings demonstrate the safety of a single infusion of MPCs in adults with type 2 diabetes and moderate to severe renal impairment. Importantly, we observed no immunological evidence of sensitization to cell therapy following a single infusion. Larger, longer duration studies are needed to confirm a signal of efficacy on renal function, as assessed by glomerular filtration rate. These studies have implications for new treatment options for diabetic kidney disease. Current treatment of diabetic nephropathy reduces progression to renal failure by only 16-25%. Multiple preclinical studies have demonstrated intravenous mesenchymal lineage cells preserve or improve renal function and histology. We report the first trial of adult, allogeneic bone-marrow derived mesenchymal precursor cells (MPCs) in adult type 2 diabetic nephropathy patients. Our findings demonstrate the safety of a single infusion of MPCs. Importantly, there was no immunological evidence of sensitization to cell therapy following a single infusion. Larger, longer studies are needed to confirm a potential signal of efficacy on renal function. Further studies of this cell therapy have implications for a new treatment option in the preservation of renal function.
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