First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency.
First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency.
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DOI：
10.1016/j.heliyon.2022.e11271
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发表时间：
2022-11
期刊：
影响因子：
4
通讯作者：
Saito, Yasushi
中科院分区：
文献类型：
--
作者：
Aso, Masayuki;Yamamoto, Tokuo T.;Kuroda, Masayuki;Wada, Jun;Kubota, Yoshitaka;Ishikawa, Ko;Maezawa, Yoshiro;Teramoto, Naoya;Tawada, Ayako;Asada, Sakiyo;Aoyagi, Yasuyuki;Kirinashizawa, Mika;Onitake, Akinobu;Matsuura, Yuta;Yasunaga, Kunio;Konno, Shun-ichi;Nishino, Katsuaki;Yamamoto, Misato;Miyoshi, Junko;Kobayashi, Norihiko;Tanio, Masami;Ikeuchi, Takayuki;Igari, Hidetoshi;Mitsukawa, Nobuyuki;Hanaoka, Hideki;Yokote, Koutaro;Saito, Yasushi
关键词：
家族性卵磷脂：胆固醇酰基转移酶（LCAT）缺乏症（FLD）是一种严重的遗传性疾病，缺乏有效的治疗。FLD患者发生严重的低HDL、角膜混浊、溶血性贫血和肾损伤。我们开发了用于离体基因治疗的分泌LCAT的遗传修饰脂肪细胞（GMAC）（LCAT-GMAC）。从患者的脂肪细胞中制备GMAC，通过逆转录病毒基因转导表达LCAT以分泌功能酶。本研究旨在评价FLD患者植入LCAT-GMAC的安全性和有效性。使用天花板培养从患者获得增殖性前脂肪细胞，并用LCAT进行逆转录病毒转导。在通过扩增培养转导的细胞获得足够的细胞后，将所得的LCAT-GMAC植入患有FLD的患者中。为了评估安全性和有效性，我们分析了24周观察期和随后240周随访期的自体植入结局。通过评估不良事件，证明这种首次人体自体植入LCAT-GMAC是安全的。LCAT-GMAC植入使血清LCAT活性增加了基线的约50%，并持续了3年。与LCAT活性增加一致，中密度脂蛋白（IDL）和游离胆固醇水平的小和非常小的HDL组分降低。我们在患者的溶血着床前血清中发现了血红蛋白/触珠蛋白复合物。植入一周后，血红蛋白/触珠蛋白复合物几乎消失。植入后，患者的蛋白尿暂时降至轻度水平，并逐渐增加至基线水平。植入后48周，患者的蛋白尿恶化，并出现轻度高血压。通过抗高血压药物治疗，病人的血压恢复正常。随着血压正常化，蛋白尿迅速下降至轻度蛋白尿水平。在患有FLD的患者中植入LCAT-GMAC被证明是安全的，并且似乎在一定程度上对治疗FLD中的贫血和蛋白尿有效。胆固醇稳态;离体基因治疗;家族性LCAT缺乏症; HDL; LCAT;蛋白尿;肾损伤。
Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient’s adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. Proliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. This first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. LCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD. Cholesterol homeostasis; Ex vivo gene therapy; Familial LCAT deficiency; HDL; LCAT; Proteinuria; Renal injury.
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DOI：
10.1093/ndtplus/sfr091
发表时间：
2011-10
期刊：
NDT plus
影响因子：
--
作者：
Katayama A;Wada J;Kataoka HU;Yamasaki H;Teshigawara S;Terami T;Inoue K;Kanzaki M;Murakami K;Nakatsuka A;Sugiyama H;Koide N;Bujo H;Makino H
通讯作者：
Makino H
影响因子：
3.7
作者：
Ji X;Feng Y;Tian H;Meng W;Wang W;Liu N;Zhang J;Wang L;Wang J;Gao H
通讯作者：
Gao H
影响因子：
3.3
作者：
Cohen P;Spiegelman BM
通讯作者：
Spiegelman BM
影响因子：
8.2
作者：
Ito, M;Bujo, H;Saito, Y
通讯作者：
Saito, Y
影响因子：
6.5
作者：
Norum, Kaare R.;Remaley, Alan T.;Retterstol, Kjetil
通讯作者：
Retterstol, Kjetil