Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.
Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.
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DOI：
10.1093/ehjopen/oead002
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
Davis, Michael E
中科院分区：
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作者：
Kaushal, Sunjay;Hare, Joshua M;Hoffman, Jessica R;Boyd, Riley M;Ramdas, Kevin N;Pietris, Nicholas;Kutty, Shelby;Tweddell, James S;Husain, S Adil;Menon, Shaji C;Lambert, Linda M;Danford, David A;Kligerman, Seth J;Hibino, Narutoshi;Korutla, Laxminarayana;Vallabhajosyula, Prashanth;Campbell, Michael J;Khan, Aisha;Naioti, Eric;Yousefi, Keyvan;Mehranfard, Danial;McClain-Moss, Lisa;Oliva, Anthony A;Davis, Michael E
左心发育不全综合征（HLHS）的生存依赖于手术重建右心室（RV）以提供体循环。这大大增加了右心室负荷、壁应力、不适应重构和功能障碍，进而增加了死亡或移植的风险。我们进行了一项1期开放标签多中心试验，以评估Lomecel-B作为二期HLHS手术姑息治疗的安全性和可行性。Lomecel-B是一种由同种异体药物信号细胞（MSCs）组成的实验性细胞疗法，通过心肌内注射给药。主要终点是安全性，并获得RV功能对潜在疗效的测量。10例患者接受了治疗。没有发生严重的心脏不良事件。在治疗后1年，所有患者都存活且无移植，并且经历了与健康历史数据相当的生长。心脏磁共振成像（CMR）通过定性评估显示三尖瓣反流分数（TR RF）改善，并在治疗后6个月和12个月从基线显著定量改善（P < 0.05）。整体纵向应变（GLS）和RV射射分数（EF）没有下降。为了了解潜在的作用机制，研究人员检查了来自心肌内移植MSCs的循环外泌体。计算模型鉴定出54种与TR RF变化相对应的msc特异性外泌体核糖核酸（rna），包括miR-215-3p、miR-374b-3p以及与细胞代谢和MAPK信号传导相关的rna。心内给药Lomecel-B在HLHS患者中似乎是安全的，并可能对RV性能产生有利影响。移植的msc特异性循环外泌体为生物活性提供了新的见解。控制阶段试验的进行是必要的，并且正在进行中。试验注册号NCT03525418。HLHS，左心发育不良综合征；MSCs，药用信号细胞；RV，右心室；RA，右心房；SVC，上腔静脉；右肺动脉；LPA，左肺动脉
Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway. Trial registration number NCT03525418. HLHS, hypoplastic left heart syndrome; MSCs, medicinal signalling cells; RV, Right Ventricular; RA, Right Atrium; SVC, Superior Vena Cava; RPA, Right Pulmonary Artery; LPA, Left Pulmonary Artery