First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency

Masayuki Aso; Tokuo T Yamamoto; Masayuki Kuroda; Jun Wada; Yoshitaka Kubota; Ko Ishikawa; Yoshiro Maezawa; Naoya Teramoto; Ayako Tawada; Sakiyo Asada; Yasuyuki Aoyagi; Mika Kirinashizawa; Akinobu Onitake; Yuta Matsuura; Kunio Yasunaga; Shun-Ichi Konno; Katsuaki Nishino; Misato Yamamoto; Junko Miyoshi; Norihiko Kobayashi; Masami Tanio; Takayuki Ikeuchi; Hidetoshi Igari; Nobuyuki Mitsukawa; Hideki Hanaoka; Koutaro Yokote; Yasushi Saito

doi:10.1016/j.heliyon.2022.e11271

First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency

Heliyon. 2022 Nov 1;8(11):e11271. doi: 10.1016/j.heliyon.2022.e11271. eCollection 2022 Nov.

Authors

Masayuki Aso¹, Tokuo T Yamamoto¹, Masayuki Kuroda², Jun Wada³, Yoshitaka Kubota⁴, Ko Ishikawa⁵, Yoshiro Maezawa⁵, Naoya Teramoto⁵, Ayako Tawada⁶, Sakiyo Asada¹, Yasuyuki Aoyagi¹, Mika Kirinashizawa¹, Akinobu Onitake¹, Yuta Matsuura¹, Kunio Yasunaga¹, Shun-Ichi Konno¹, Katsuaki Nishino¹, Misato Yamamoto¹, Junko Miyoshi¹, Norihiko Kobayashi¹, Masami Tanio¹, Takayuki Ikeuchi⁷, Hidetoshi Igari⁸, Nobuyuki Mitsukawa⁴, Hideki Hanaoka⁷, Koutaro Yokote⁵, Yasushi Saito⁹

Affiliations

¹ CellGenTech, Inc., 2600856 Chiba, Japan.
² Center for Advanced Medicine, Chiba University Hospital, 2608677 Chiba, Japan.
³ Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 7008530 Okayama, Japan.
⁴ Department of Plastic and Reconstructive Surgery, Chiba University, Faculty of Medicine, 2608670 Chiba, Japan.
⁵ 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.
⁶ Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 2608670 Chiba, Japan.
⁷ Chiba University Hospital Clinical Research Center, 2608677 Chiba, Japan.
⁸ Division of Infection Control, Chiba University Hospital, 2608677 Chiba, Japan.
⁹ Chiba University, 2608670 Chiba, Japan.

Abstract

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.

Keywords: Cholesterol homeostasis; Ex vivo gene therapy; Familial LCAT deficiency; HDL; LCAT; Proteinuria; Renal injury.