Wittenberg Rachel E, Gauvreau Kimberlee, Leighton Jonah, Moleon-Shea Melinda, Borow Kenneth M, Marx Gerald R, Emani Sitaram M
Harvard Medical School, Boston, Mass.
Department of Cardiology, Boston Children's Hospital, Boston, Mass.
JTCVS Open. 2023 Oct 1;16:656-672. doi: 10.1016/j.xjon.2023.09.031. eCollection 2023 Dec.
To assess the safety and feasibility of low-dose, novel, allogenic mesenchymal precursor cell (MPC) therapy as an adjunct to left ventricular (LV) recruitment for patients with hypoplastic left heart syndrome (HLHS) and borderline left ventricles. MPC injections into the hypoplastic left ventricle may stimulate neovascularization and beneficial LV remodeling and may improve the likelihood of achieving biventricular (BiV) or 1.5 ventricle (1.5V) circulation.
Children <5 years with prior single ventricle palliation undergoing LV recruitment surgery at a single center were randomized to MPC injections into the LV endocardium/papillary muscles (MPCs) or standard-of-care (controls) and followed for 24 months. The primary endpoint was safety, including (serious) adverse events (S/AEs), and panel reactive antibodies (PRAs). Secondary endpoints included BiV/1.5V conversion and LV size and function.
Nineteen subjects were enrolled, including 9 MPC recipients and 10 controls. Fourteen patients (74%) had >1 AE, and 2 patients had SAEs, both deemed unrelated to the trial product. AE severity and frequency were similar in the 2 groups. Baseline PRA levels were high, with no difference between the groups at 12 months. The overall probability of BiV/1.5V conversion was 0.16 (95% confidence interval [CI], 0.05 to 0.41) at 12 months and 0.52 (95% CI, 0.31 to 0.77) at 24 months. For patients with imaging data at both time points, increases in LV volumes from baseline to 12 months were larger in the MPC group by 3-dimensional echocardiography and cardiac magnetic resonance imaging. For children who successfully underwent BiV conversion (n = 12), full BiV conversion was achieved at 24 months in 5 of 5 (100%) MPC-treated children compared with 4 of 7 (57%) controls.
MPC injections were considered safe and feasible in HLHS patients. More than 50% of subjects underwent BiV/1.5V conversion within 2 years. Larger trials are needed to investigate the therapeutic potential of MPCs in this population.
评估低剂量、新型异体间充质前体细胞（MPC）疗法作为左心发育不全综合征（HLHS）和临界左心室患者左心室（LV）恢复辅助治疗的安全性和可行性。向发育不全的左心室内注射MPC可能会刺激新血管形成和有益的左心室重塑，并可能提高实现双心室（BiV）或1.5心室（1.5V）循环的可能性。
在单一中心接受LV恢复手术的5岁以下曾接受单心室姑息治疗的儿童被随机分为向左心内膜/乳头肌注射MPC（MPC组）或标准治疗组（对照组），并随访24个月。主要终点是安全性，包括（严重）不良事件（S/AEs）和群体反应性抗体（PRA）。次要终点包括BiV/1.5V转换以及左心室大小和功能。
共纳入19名受试者，其中9名接受MPC治疗，10名作为对照。14名患者（74%）发生>1次不良事件，2名患者发生严重不良事件，均被认为与试验产品无关。两组不良事件的严重程度和发生率相似。基线时PRA水平较高，12个月时两组之间无差异。12个月时BiV/1.5V转换的总体概率为0.16（95%置信区间[CI]，0.05至0.41），24个月时为0.52（95%CI，0.31至0.77）。对于在两个时间点均有影像学数据的患者，通过三维超声心动图和心脏磁共振成像显示，MPC组从基线到12个月左心室容积的增加幅度更大。对于成功接受BiV转换的儿童（n = 12），在24个月时，5名接受MPC治疗的儿童中有5名（100%）实现了完全BiV转换，而对照组7名儿童中有4名（57%）实现了完全BiV转换。
在HLHS患者中，MPC注射被认为是安全可行的。超过50%的受试者在2年内实现了BiV/1.5V转换。需要进行更大规模的试验来研究MPC在该人群中的治疗潜力。
