首次将表达卵磷脂胆固醇酰基转移酶（LCAT）的基因修饰脂肪细胞自体植入人体用于治疗家族性LCAT缺乏症。
First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency.
作者信息
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
机构信息
CellGenTech, Inc., 2600856 Chiba, Japan.
Center for Advanced Medicine, Chiba University Hospital, 2608677 Chiba, Japan.
出版信息
Heliyon. 2022 Nov 1;8(11):e11271. doi: 10.1016/j.heliyon.2022.e11271. eCollection 2022 Nov.
BACKGROUND
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.
OBJECTIVE
We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for 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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
背景
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，尚无有效治疗方法。FLD患者会出现严重的低高密度脂蛋白（HDL）、角膜混浊、溶血性贫血和肾损伤。
目的
我们开发了分泌LCAT的基因修饰脂肪细胞（LCAT-GMAC）用于基因治疗。通过逆转录病毒基因转导从患者脂肪细胞制备GMAC以表达LCAT，从而分泌功能性酶。本研究旨在评估LCAT-GMAC植入FLD患者的安全性和有效性。
方法
使用天花板培养法从患者获取增殖性前脂肪细胞，并用LCAT进行逆转录病毒转导。通过对转导细胞进行扩增培养获得足够数量的细胞后，将所得的LCAT-GMAC植入一名FLD患者体内。为评估安全性和有效性，我们分析了自体植入24周观察期及随后240周随访期的结果。
结果
通过评估不良事件，首次人体自体植入LCAT-GMAC显示是安全的。LCAT-GMAC植入使血清LCAT活性增加了约基线水平的50%，并持续了三年。与LCAT活性增加一致，中小和极小HDL组分的中间密度脂蛋白（IDL）和游离胆固醇水平降低。我们在患者植入前溶血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。植入后患者蛋白尿立即暂时降至轻度水平，并逐渐升至基线。植入后48周，患者蛋白尿随着轻度高血压的出现而恶化。通过使用抗高血压药物治疗，患者血压恢复正常。随着血压正常化，蛋白尿迅速降至轻度蛋白尿水平。
结论
LCAT-GMAC植入FLD患者显示是安全的，并且似乎部分有效地治疗了FLD中的贫血和蛋白尿。
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