Center for Advanced Medicine, Chiba University Hospital, 2608677 Chiba, Japan
Jun Wada
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 7008530 Okayama, Japan
Yoshitaka Kubota
Department of Plastic and Reconstructive Surgery, Chiba University, Faculty of Medicine, 2608670 Chiba, Japan
Ko Ishikawa
Department of Endocrinology, Hematology, and Gerontology, Chiba University, Graduates School of Medicine and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, 2608670 Chiba, Japan
Yoshiro Maezawa
Department of Endocrinology, Hematology, and Gerontology, Chiba University, Graduates School of Medicine and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, 2608670 Chiba, Japan
Naoya Teramoto
Department of Endocrinology, Hematology, and Gerontology, Chiba University, Graduates School of Medicine and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, 2608670 Chiba, Japan
Ayako Tawada
Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 2608670 Chiba, Japan
Sakiyo Asada
CellGenTech, Inc., 2600856 Chiba, Japan
Yasuyuki Aoyagi
CellGenTech, Inc., 2600856 Chiba, Japan
Mika Kirinashizawa
CellGenTech, Inc., 2600856 Chiba, Japan
Akinobu Onitake
CellGenTech, Inc., 2600856 Chiba, Japan
Yuta Matsuura
CellGenTech, Inc., 2600856 Chiba, Japan
Kunio Yasunaga
CellGenTech, Inc., 2600856 Chiba, Japan
Shun-ichi Konno
CellGenTech, Inc., 2600856 Chiba, Japan
Katsuaki Nishino
CellGenTech, Inc., 2600856 Chiba, Japan
Misato Yamamoto
CellGenTech, Inc., 2600856 Chiba, Japan
Junko Miyoshi
CellGenTech, Inc., 2600856 Chiba, Japan
Norihiko Kobayashi
CellGenTech, Inc., 2600856 Chiba, Japan
Masami Tanio
CellGenTech, Inc., 2600856 Chiba, Japan
Takayuki Ikeuchi
Chiba University Hospital Clinical Research Center, 2608677 Chiba, Japan
Hidetoshi Igari
Division of Infection Control, Chiba University Hospital, 2608677 Chiba, Japan
Nobuyuki Mitsukawa
Department of Plastic and Reconstructive Surgery, Chiba University, Faculty of Medicine, 2608670 Chiba, Japan
Hideki Hanaoka
Chiba University Hospital Clinical Research Center, 2608677 Chiba, Japan
Koutaro Yokote
Department of Endocrinology, Hematology, and Gerontology, Chiba University, Graduates School of Medicine and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, 2608670 Chiba, Japan; Corresponding author.
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 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. 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.
