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3 results on '"Akinobu Onitake"'

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

Author

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, and Yasushi Saito

Subjects
Cholesterol homeostasis, Ex vivo gene therapy, Familial LCAT deficiency, HDL, LCAT, Proteinuria, Science (General), Q1-390, Social sciences (General), H1-99
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.

Published
2022
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2. The C-terminal α-helix of SPAS-1, a Caenorhabditis elegans spastin homologue, is crucial for microtubule severing

Author

Kunitoshi Yamanaka, Ai Johjima, Teru Ogura, Masatoshi Esaki, Akinobu Onitake, and Yuka Matsushita-Ishiodori

Subjects
Subfamily, biology, Seminal Plasma Proteins, Katanin, macromolecular substances, Spastin, biology.organism_classification, Microtubules, AAA proteins, Cell Line, Mitochondrial Proteins, Spectrometry, Fluorescence, Biochemistry, Structural Biology, Microtubule, Chaperone (protein), Chromatography, Gel, biology.protein, Animals, Humans, Caenorhabditis elegans Proteins, Caenorhabditis elegans, Microtubule severing
Abstract

Spastin belongs to the meiotic subfamily, together with Vps4/SKD1, fidgetin and katanin, of AAA (ATPases associated with diverse cellular activities) proteins, and functions in microtubule severing. Interestingly, all members of this subgroup specifically contain an additional α-helix at the very C-terminal end. To understand the function of the C-terminal α-helix, we characterised its deletion mutants of SPAS-1, a Caenorhabditis elegans spastin homologue, in vitro and in vivo. We found that the C-terminal α-helix plays essential roles in ATP binding, ATP hydrolysing and microtubule severing activities. It is likely that the C-terminal α-helix is required for cellular functions of members of meiotic subgroup of AAA proteins, since the C-terminal α-helix of Vps4 is also important for assembly, ATPase activity and in vivo function mediated by ESCRT-III complexes.

Published
2012
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3. Caenorhabditis elegans fidgetin homolog FIGL-1, a nuclear-localized AAA ATPase, binds to SUMO

Author

Akinobu, Onitake, Kunitoshi, Yamanaka, Masatoshi, Esaki, and Teru, Ogura

Subjects
Adenosine Triphosphatases, Cell Nucleus, Ubiquitin, Two-Hybrid System Techniques, SUMO-1 Protein, Animals, Humans, Immunoprecipitation, Nuclear Proteins, Caenorhabditis elegans Proteins, Immunohistochemistry, Protein Binding
Abstract

Fidgetin is a member of the AAA (ATPases associated with diverse cellular activities) chaperones. It is well-known that the specific function of a given AAA protein primarily depends upon its subcellular localization and interacting partners. FIGL-1, a Caenorhabditis elegans homolog of mammalian fidgetin, is localized in the nucleus. Here, we identified that the N-terminal PKRVK sequence of FIGL-1 functions as a monopartite nuclear localization signal. Nuclear localization of FIGL-1 is required for its function. We also found that FIGL-1 specifically interacted with SMO-1, a C. elegans homolog of small ubiquitin-like modifier (SUMO), using a yeast two-hybrid assay. Furthermore, the direct physical interaction between FIGL-1 and SMO-1 was demonstrated by pull-down assay using purified proteins as well as immunoprecipitation assay using lysates from epitope-tagged SMO-1-expressing worms. Binding of FIGL-1 to SMO-1 is required for its function. The depletion of FIGL-1 and SMO-1 resulted in developmental defects in C. elegans. Taken altogether, our results indicate that FIGL-1 is a nuclear protein and that in concert with SMO-1, FIGL-1 plays an important role in the regulation of C. elegans development.

Published
2012

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