Intraperitoneal transplant of Hepatocytes co-Encapsulated with mesenchymal stromal cells in modified alginate microbeads for the treatment of acute Liver failure in Pediatric patients (HELP)-An open-label, single-arm Simon's two stage phase 1 study protocol.
Intraperitoneal transplant of Hepatocytes co-Encapsulated with mesenchymal stromal cells in modified alginate microbeads for the treatment of acute Liver failure in Pediatric patients (HELP)-An open-label, single-arm Simon's two stage phase 1 study protocol.
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DOI：
10.1371/journal.pone.0288185
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
小儿急性肝衰竭（PALF）在不进行肝移植（LT）的情况下具有较高的死亡率。肝移植虽然可以挽救生命，但受到供体器官及时可用性、大手术风险和终身免疫抑制并发症的限制。肝细胞移植（HT）改善小动物模型的合成和解毒功能。藻酸盐中肝细胞的包封保护其免受受体免疫系统的影响，而腹膜内给药途径允许大量输注。已在指定患者使用中观察到包封肝细胞的安全性和可能的短期疗效。利用改性藻酸盐和间充质基质细胞（MSC），开发了一种新型微珠（HMB 002）。其安全性和中期疗效需要在临床研究的背景下进行研究，同时使用藻酸盐和MSC共包封的修饰来优化肝细胞功能和活力。将进行单中心、非随机、开放标签、单臂Simon两阶段研究，以评价在17名年龄小于16岁的急性肝功能衰竭患者（第1阶段：9名患者和第2阶段：8名患者）中移植单次腹膜内剂量的微珠的安全性、生物活性和耐受性，所述微珠由改性藻酸盐、MSC和肝细胞的最佳组合制成。将通过记录术后前52周内HMB 002导致的中度至重度（包括危及生命和死亡）不良事件来评估安全性。通过观察患者接受>80%输注的起始输注比例来评估耐受性。生物活性将反映在治疗后24周具有天然肝脏的患者存活率中。如果HMB 002在急性肝功能衰竭中安全有效，则可以成为肝脏再生或合适器官可用的桥梁。使用HT有很多优点。HT，当通过腹膜内途径递送时，比LT具有更小的侵入性。来自单个供体肝脏的肝细胞可用于治疗多个患者。冷冻保存的细胞为PALF提供了现成的紧急治疗。当包封时，肝细胞的藻酸盐包封排除了与LT中不同的免疫抑制的需要。
Pediatric acute liver failure (PALF) carries a high mortality without liver transplantation (LT) in children. Liver transplantation, though lifesaving, is limited by timely donor organ availability, the risks of major surgery and complications of life-long immunosuppression. Hepatocyte transplantation (HT) improves synthetic and detoxification functions in small animal models. The encapsulation of hepatocytes in alginate protects it from the recipient immune system while the intraperitoneal route of administration allows large volumes to be infused. The safety and possibly short-term efficacy of encapsulated hepatocytes has been observed in a named patient use. A novel type of microbeads (HMB002) has been developed, using a modified alginate and mesenchymal stromal cells (MSCs). Its safety and medium-term efficacy need to be studied in the context of clinical study while optimizing the hepatocyte function and viability using modifications of the alginate and MSCs co-encapsulation. A single centre, non-randomised, open-label, single-arm Simon’s two stage study will be conducted to evaluate the safety, biological activity and tolerability of transplantation of a single intraperitoneal dose of microbeads made from an optimum combination of a modified alginate, MSCs and hepatocytes in 17 patients less than 16 years of age with acute liver failure (Stage 1: 9 patients and Stage 2: 8 patient). Safety will be assessed by documenting moderate to severe (including life threatening and death) adverse events due to HMB002 in the first 52 weeks post-procedure. Tolerability will be assessed by observing the proportion of initiated infusions where >80% of infusion is received by the patient. Biological activity will be reflected in patient survival with native liver at 24 weeks post treatment. HMB002, if safe and efficacious in acute liver failure, could be a bridge until the liver regenerates or a suitable organ becomes available. There are multiple advantages to using HT. HT, when delivered by the intraperitoneal route, is less invasive than LT. Hepatocytes from a single donor liver can be used to treat multiple patients. Cryopreserved cells provide an off-the-shelf emergency treatment in PALF. When encapsulated, alginate encapsulation of hepatocytes precludes the need for immunosuppression unlike in LT.
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影响因子：
9
作者：
Faraj, Walid;Dar, Faisal;Rela, Mohamed
通讯作者：
Rela, Mohamed
影响因子：
3.3
作者：
Fitzpatrick, Emer;Wu, Yue;Dhawan, Anil
通讯作者：
Dhawan, Anil
影响因子：
25.7
作者：
Dhawan, Anil;Chaijitraruch, Nataruks;Mitry, Ragai R.
通讯作者：
Mitry, Ragai R.
影响因子：
3.9
作者：
Iansante V;Dhawan A;Masmoudi F;Lee CA;Fernandez-Dacosta R;Walker S;Fitzpatrick E;Mitry RR;Filippi C
通讯作者：
Filippi C
影响因子：
3.7
作者：
Jitraruch S;Dhawan A;Hughes RD;Filippi C;Soong D;Philippeos C;Lehec SC;Heaton ND;Longhi MS;Mitry RR
通讯作者：
Mitry RR