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
The Heart Center, Division of Cardiovascular-Thoracic Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Chicago, IL 60611, USA.
Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA.
Eur Heart J Open. 2023 Jan 11;3(2):oead002. doi: 10.1093/ehjopen/oead002. eCollection 2023 Mar.
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 ( < 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.
左心发育不全综合征（HLHS）患者的存活依赖于右心室（RV）的外科重建以提供体循环。这会显著增加右心室负荷、壁应力、适应性不良重塑和功能障碍，进而增加死亡或移植风险。
我们开展了一项1期开放标签多中心试验，以评估Lomecel - B作为二期HLHS外科姑息治疗辅助手段的安全性和可行性。Lomecel - B是一种由同种异体药用信号细胞（MSC）组成的研究性细胞疗法，通过心肌内注射给药。主要终点是安全性，并获取了右心室功能指标以评估潜在疗效。10名患者接受了治疗。无人发生重大不良心脏事件。所有患者在治疗后1年时均存活且未接受移植，生长情况与健康历史数据相当。心脏磁共振成像（CMR）通过定性评估者评估提示三尖瓣反流分数（TR RF）有所改善，且在治疗后6个月和12个月时与基线相比有显著的定量改善（<0.05）。整体纵向应变（GLS）和右心室射血分数（EF）未下降。为了解潜在作用机制，对心肌内移植的MSC释放的循环外泌体进行了检测。计算模型确定了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。
心肌内注射Lomecel - B在HLHS患者中似乎是安全的，并且可能对右心室功能产生有利影响。移植的MSC特异性循环外泌体为生物活性提供了新的见解。有必要且正在进行一项对照试验。试验注册号NCT03525418。
