Hepatocyte replacement therapy for familial amybidotic polyneuropathy combining iPS cells and gene-repair therapy

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390270
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: ANDO Yukio 熊本大学, 大学院・生命科学研究部, 教授 (20253742)
• Co-Investigator(Kenkyū-buntansha): KUME Shoen 熊本大学, 発生医学研究所, 教授 (70347011) ; JONO Hirofumi 熊本大学, 大学院・生命科学研究部, 講師 (40515483) ; UEDA Mitsuharu 熊本大学, 大学院・生命科学研究部, 助教 (60452885)
• Co-Investigator(Renkei-kenkyūsha): SHIRAKI Nobuaki 熊本大学, 発生医学研究所, 助教 (70448520)
• Project Period (FY): 2009 – 2011
• Keywords: iPS細胞 / 家族性アミロイドポリニューロパチー / トランスサイレチン / 点変異修復 / 肝細胞置換療法

Research Abstract

From April, 2009 to March, 2012, to develop a curative treatment for familial amyloidotic polyneuropathy(FAP), we obtained somatic cells from FAP patients or transgenic rats possessing a human ATTR V30M gene(ATTR V30M Tg rats) and reprogrammed to pluripotency to generate FAP-specific induced pluripotent stem(iPS) cells, and evaluated the possibility of hepatocyte replacement therapy combining FAP-specific iPS cells and gene-repair therapy using single stranded oligonucleotides(SSOs). In the next project, we will focus on using these FAP-specific iPS cells to elucidate the precise pathogenesis of FAP, improve the efficiency of gene conversion rate, and determine the availability of hepatocyte replacement therapy in the in vivo experiments using ATTR V30M Tg rats, an existing useful FAP animal model.

Research Products

• [Journal Article] Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy (2012)
  • Author(s): Misumi Y, Ueda M, Obayashi K, Jono H, Su Y, Yamashita T, Ohshima T, Ando Y, Uchino M
  • Journal Title: Hum Pathol Volume: 43 Pages: 96-104
  • Peer Reviewed
• [Journal Article] The occurrence of islet amyloid polypeptide amyloidosis in Japanese subjects (2012)
  • Author(s): Su Y, Misumi Y, Ueda M, Shono M, Tasaki M, Guo J, Jono H, Obayashi K, Senokuchi T, Yamagata K, Ando Y
  • Journal Title: Pancreas Volume: (in press)
  • Peer Reviewed
• [Journal Article] Potential Use of Lactosylated Dendrimer(G3)/α-Cyclodextrin Conjugates as Hepatocyte-Specific siRNA Carriers for the Treatment of Familial Amyloidotic Polyneuropathy (2012)
  • Author(s): Hayashi Y, Mori Y, Yamashita S, Motoyama K, Higashi T, Jono H, Ando Y, Arima H
  • Journal Title: Mol Pharm Volume: (in press)
  • Peer Reviewed
• [Journal Article] Aged vervet monkeys developing transthyretin amyloidosis with thehuman disease-causing Ile122 allele : A valid pathological model of the human disease (2012)
  • Author(s): Ueda M, Ageyama N, Nakamura S, Nakamura M, Chambers J, Misumi Y, Mizuguchi M, Shinriki S, Kawahara S, Tasaki T, Jono H, Obayashi K, Sasaki E, Une Y, Ando Y
  • Journal Title: Lab Invest Volume: (in press)
  • Peer Reviewed
• [Journal Article] Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy (2012)
  • Author(s): Yamashita T, Ando Y, Okamoto S, Misumi Y, Hirahara T, Ueda M, Obayashi K, Nakamura M, Jono H, Shono M, Asonuma K, Inomata T, Uchino M
  • Journal Title: Neurology Volume: (in press)
  • Peer Reviewed
• [Journal Article] 臨床化学からみたアミロイドーシス (2012)
  • Author(s): 大林光念、安東由喜雄
  • Journal Title: 臨床化学 Volume: 41 Pages: 4
• [Journal Article] 質量分析法を用いた新たなアミロイドーシスの診断法 (2012)
  • Author(s): 田崎義雅、安東由喜雄
  • Journal Title: 臨床化学 Volume: 41 Pages: 41-46
• [Journal Article] Sensorimotor manifestations without autonomic symptoms in two siblings with TTR Val107 familial amyloid polyneuropathy (2011)
  • Author(s): Asahina M, Akaogi Y, Misawa S, Kanai K, Ando Y, Sakakibara R, Arai K, Hattori T, Kuwabara S
  • Journal Title: Clin NeurolNeurosurg Volume: 113 Pages: 139-141
  • Peer Reviewed
• [Journal Article] Hereditary Gelsolin Amyloidosis : a New Japanese Case with Cutis Laxa as a Diagnostic Clue (2011)
  • Author(s): Asahina A, Yokoyama T, Ueda M, Ando Y, Ohshima N, Saito I, Tadokoro E, Hasegawa K
  • Journal Title: Acta Derm Venereol Volume: 91 Pages: 201-203
  • Peer Reviewed
• [Journal Article] Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis (2011)
  • Author(s): Jono H, Anno T, Motoyama K, Misumi Y, Tasaki T, Oshima T, Mori Y, Mizuguchi M, Ueda M, Shono M, Obayashi K, Arima H, Ando Y
  • Journal Title: Biochem J Volume: 437 Pages: 35-42
  • Peer Reviewed
• [Journal Article] Systemic but asymptomatictransthyretin amyloidosis 8 years afterdomino liver transplantation (2011)
  • Author(s): Koike H, Kiuchi T, Iijima M, UedaM, Ando Y, Morozumi S, Tomita M, Kawagashira Y, Watanabe H, Katsuno M, Shimoyama Y, Okazaki Y, Kamei H, SobueG
  • Journal Title: J NeurolNeurosurg Psychiatry Volume: 82 Pages: 1287-1290
  • Peer Reviewed
• [Journal Article] Loss of functional albumin triggersacceleration of transthyretin amyloidfibril formation in familial amyloidotic polyneuropathy (2011)
  • Author(s): Kugimiya T, Jono H, Saito S, Maruyama T, Kadowaki D, Misumi T, HoshiiY, Tasaki M, Su Y, Ueda M, Obayashi K, Shono M, Otagiri M, Ando Y
  • Journal Title: Lab Invest Volume: 91 Pages: 1219-1228
  • Peer Reviewed
• [Journal Article] Renalamyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence (2011)
  • Author(s): Morizane R, Monkawa T, Konishi K, Hashiguchi A, Ueda M, Ando Y, TokuyamaH, Hayashi K, Hayashi M, Itoh H
  • Journal Title: Clin Exper Nephorol Volume: 15 Pages: 774-779
  • Peer Reviewed
• [Journal Article] In vitro gene delivery mediated by lactosylated dendrimer(generation 3, G3)/α-cyclodextrin conjugates into hepatocytes (2011)
  • Author(s): Motoyama K, Mori Y, Yamashita S, Hayashi Y, Jono H, Ando Y, Hirayama F, Uekama K, Arima H
  • Journal Title: J Inclu Phenom MacroChem Volume: 70 Pages: 333-338
  • Peer Reviewed
• [Journal Article] Amyloid neuropathy in a younger domino liver-transplanted recipient (2011)
  • Author(s): Obayashi K, Yamashita T, Tasaki M, Ueda M, Shono M, Jono H, Ohshima T, Ohya Y, Asonuma K, Inomata Y, Ando Y
  • Journal Title: Muscle Nerve Volume: 43 Pages: 449-450
  • Peer Reviewed
• [Journal Article] Blood pressure overshoot after tilt reversal in patients with familial amyloidotic polyneuropathy (2011)
  • Author(s): Obayashi K, Hornsten R, Wiklund U, Karlsson M, Okamoto S, Ando Y, Suhr OB
  • Journal Title: Hypertens Res Volume: 34 Pages: 133-138
  • Peer Reviewed
• [Journal Article] Manifestations of Transthyretin Related Familial Amyloidotic Polyneuropathy : Long-term Follow-up of Japanese Patients after Liver Transplantation (2011)
  • Author(s): Ohya Y, Okamoto S, Tasaki M, Ueda M, Jono H, Obayashi K, Takeda K, Okajima H, Asonuma K, Hara R, Tanihara H, Ando Y, Inomatal Y
  • Journal Title: Surg Today Volume: 41 Pages: 1211-1218
  • Peer Reviewed
• [Journal Article] Wild-type transthyretin-derived amyloidosis in various ligaments and tendons (2011)
  • Author(s): Sueyoshi T, Ueda M, Jono H, Irie H, Sei A, Ide J, Ando Y, Mizuta H
  • Journal Title: Human Pathol Volume: 42 Pages: 1259-1264
  • Peer Reviewed
• [Journal Article] Spinal multifocal amyloidosis derived from wild-type transthyretin (2011)
  • Author(s): Sueyoshi T, Ueda M, Sei A, Misumi Y, Oshima T, Yamashita T, Obayashi K, Shinriki S, Jono H, Shono M, Ando Y, Mizuta H
  • Journal Title: Amyloid Volume: 18 Pages: 165-168
  • Peer Reviewed
• [Journal Article] Clinicopathologicalfeatures of senile systemic amyloidosis : an ante-and post-mortem study (2011)
  • Author(s): Ueda M, Horibata Y, Shono M, Misumi Y, Oshima T, Su Y, Tasaki M, Shinriki S, Kawahara S, Jono H, Obayashi K, Ogawa H, Ando Y
  • Journal Title: Mod Pathol Volume: 24 Pages: 1533-1544
  • Peer Reviewed
• [Journal Article] 内科医が知っておくべき検査の最新情報:臨床検査の進歩注目される新しい検査を中心に神経内科疾患 (2011)
  • Author(s): 安東由喜雄、大林光念、植田光晴
  • Journal Title: 日本内科学会雑誌 Volume: 100 Pages: 3276-3283
• [Journal Article] 家族性アミロイドポリニューロパチー(FAP) (2011)
  • Author(s): 山下太郎、安東由喜雄、内野誠
  • Journal Title: 脳と神経 Volume: 63 Pages: 583-595
• [Journal Article] 家族性アミロイドポリニューロパチー(FAP)の治療法の進歩 (2011)
  • Author(s): 安東由喜雄
  • Journal Title: 神経治療学会誌 Volume: 28 Pages: 115-120
• [Journal Article] Investigation of AGE, their receptor and NF-kappaB activationand apoptosis in patients with ATTR andGelsolin amyloidosis (2010)
  • Author(s): Anan I, Kiuru-Enari S, Obayashi K, Ranlov PJ, Ando Y
  • Journal Title: Histol Histopathol Volume: 25 Pages: 691-699
  • Peer Reviewed
• [Journal Article] In vitro and in vivo gene delivery mediated by Lactosylateddendrimer/alpha-cyclodextrin conjugates(G2) into hepatocytes (2010)
  • Author(s): Arima H, Yamashita S, Mori Y, Hayashi Y, Motoyama K, Hattori K, Takeuchi T, Jono H, Ando Y, Hirayama F, Uekama K
  • Journal Title: J Control Release Volume: 146 Pages: 106-117
  • Peer Reviewed
• [Journal Article] Impact of Liver Transplantation on Transthyretin related Ocular Amyloidosis in Japanese Patients (2010)
  • Author(s): Hara R, Kawaji T, Ando E, Ohya Y, Ando Y, Tanihara H
  • Journal Title: Arch Ophthalmol Volume: 128 Pages: 206-210
  • Peer Reviewed
• [Journal Article] Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy (2010)
  • Author(s): Hirohata M, Yoshita M, Ishida C, Ikeda SI, Tamaoka A, Kuzuhara S, Shoji M, Ando Y, Tokuda T, Yamada M
  • Journal Title: Eur J Neurol Volume: 17 Pages: 823-829
  • Peer Reviewed
• [Journal Article] Novel therapy for transthyretin-related ocular amyloidosis : a pilot study of retinal laser photocoagulation (2010)
  • Author(s): Kawaji T, Ando Y, Hara R, Tanihara H
  • Journal Title: Ophthalmology Volume: 117 Pages: 552-555
  • Peer Reviewed
• [Journal Article] Transthyretin related vitreous amyloidosis in different endemic areas (2010)
  • Author(s): Kawaji T, Ando Y, Ando E, Sandgren O, Suhr OB
  • Journal Title: Amyloid Volume: 17 Pages: 105-108
  • Peer Reviewed
• [Journal Article] A case of familial amyloid polyneuropathy due to Phe33Val TTR with vitreous involvement as the initial manifestation (2010)
  • Author(s): Kono S, Manabe Y, Tanaka T, Fujii D, Sakai Y, Narai H, Omori N, Ueda M, Ando Y, Abe K
  • Journal Title: Intern Med Volume: 49 Pages: 1213-1216
  • Peer Reviewed
• [Journal Article] Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding (2010)
  • Author(s): Miyata M, Sato T, Mizuguchi M, Nakamura T, Ikemizu S, Nabeshima Y, Susuki S, Suwa Y, Morioka H, Ando Y, Suico MA, Shuto T, Koga T, Yamagata Y, Kai H
  • Journal Title: Biochemistry Volume: 49 Pages: 114-123
  • Peer Reviewed
• [Journal Article] Gastric myoelectrical activities in elderly severe tetanus : Useful marker to increase volume and calorie of nasogastric tube feeding (2010)
  • Author(s): Obayashi K, Ueda M, Yamashita T, Misumi Y, Hirahara T, Tasaki M, Ohshima T, Uchino M, Ando Y
  • Journal Title: e-SPEN Volume: 5 Pages: e261-e264
  • Peer Reviewed
• [Journal Article] Effect of recipient-derived cells on the progression of familial amyloidotic polyneuropathy after liver transplantation : a retrospective study (2010)
  • Author(s): Ohya Y, Jono H, Nakamura M, Hayashida S, Ueda M, Obayashi K, Misumi S, Asonuma K, Ando Y, Inomata Y
  • Journal Title: Ann Clin Biochem Volume: 47 Pages: 529-534
  • Peer Reviewed
• [Journal Article] Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism (2010)
  • Author(s): Tasaki M, Ueda M, Ochiai S, Tanabe Y, Murata S, Misumi Y, Su Y, Sun X, Shinriki S, Jono H, Shono M, Obayashi K, Ando Y
  • Journal Title: Biochem Biopys Res Commun Volume: 400 Pages: 559-562
  • Peer Reviewed
• [Journal Article] Mouse model to study human A beta2M amyloidosis : generation of a transgenic mouse with excessive expression of human beta2-microglobulin (2010)
  • Author(s): Zhang P, Fu X, Sawashita J, Yao J, Zhang B, Qian J, Tomozawa H, Mori M, Ando Y, Naiki H, Higuchi K
  • Journal Title: Amyloid Volume: 17 Pages: 50-62
  • Peer Reviewed
• [Journal Article] 知って得する最新情報「家族性アミロイドポリニューロパチー(FAP)」 (2010)
  • Author(s): 安東由喜雄
  • Journal Title: Clinical Neuroscience Volume: 28 Pages: 224-225
• [Journal Article] 血清アルブミンとトランスサイレチン (2010)
  • Author(s): 安東由喜雄、大林光念
  • Journal Title: 臨床と研究 Volume: 87 Pages: 39-43
• [Journal Article] 老化とアミロイドーシス (2010)
  • Author(s): 安東由喜雄
  • Journal Title: 熊本医学会ニューズレター Volume: 8 Pages: 22-28
• [Journal Article] アミロイド蛋白への治療アプローチ-家族性アミロイドポリニューロパチーをモデルとして- (2010)
  • Author(s): 大林光念、安東由喜雄
  • Journal Title: 生物物理化学 Volume: 54 Pages: 23-25
• [Journal Article] 遺伝性アミロイドーシスの診断と病態解析における質量分析法の有用性 (2010)
  • Author(s): 植田光晴、安東由喜雄
  • Journal Title: JSBMS Letters Volume: 35 Pages: 48-54
  • Peer Reviewed
• [Journal Article] Distinct characteristics of amyloid deposits in early-and late-onset transthyretin Val30Met familial amyloid polyneuropathy (2009)
  • Author(s): Koike H, Ando Y, Ueda M, Kawagashira Y, Iijima M, Fujitake J, Hayashi M, Yamamoto M, Mukai E, Nakamura T, Katsuno M, Hattori N, Sobue G
  • Journal Title: J Neurol Sci Volume: 287 Pages: 178-184
  • Peer Reviewed
• [Journal Article] Chain reaction of amyloid fibril formation with induction of basement membrane in familial amyloidotic polyneuropathy (2009)
  • Author(s): Misumi Y, Ando Y, Ueda M, Obayashi K, Jono H, Su Y, Yamashita T, Uchino M
  • Journal Title: J Pathol Volume: 219 Pages: 481-490
  • Peer Reviewed
• [Journal Article] Liver transplantation for familial amyloidotic polyneuropathy : impact on Swedish patients' survival (2009)
  • Author(s): Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, Uchino M, Suhr OB
  • Journal Title: Liver Transpl Volume: 15 Pages: 1229-1235
  • Peer Reviewed
• [Journal Article] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells (2009)
  • Author(s): Susuki S, Sato T, Miyata M, Momohara M, Suico MA, Shuto T, Ando Y, Kai H
  • Journal Title: J Biol Chem Volume: 284 Pages: 8312-8321
  • Peer Reviewed
• [Journal Article] Excessive fibrinogenesis in AL-amyloidosis is induced by urokinae-type plasminogen activator from bone marrow plasma cells (2009)
  • Author(s): Uchiba M, Imamura T, Hata H, Tatetsu H, Yonemura Y, Ueda M, Wada Y, Mitsuya H, Ando Y
  • Journal Title: Amyloid Volume: 16 Pages: 89-93
  • Peer Reviewed
• [Journal Article] SELDI-TOF mass spectrometry evaluation of variant transthyretins for diagnosis and pathogenesis of familial amyloidotic polyneuropathy (2009)
  • Author(s): Ueda M, Misumi Y, Mizuguchi M, Nakamura M, Yamashita T, Sekijima Y, Ota K, Shinriki S, Jono H, Ikeda S, Suhr OB, Ando Y
  • Journal Title: Clin Chem Volume: 55 Pages: 1223-1227
  • Peer Reviewed
• [Journal Article] A Circulating beta2-Microglobulin Intermediate in Hemodialysis Patients (2009)
  • Author(s): Uji Y, Motomiya Y, Ando Y
  • Journal Title: Nephron Clin Pract Volume: 111 Pages: 173-181
  • Peer Reviewed
• [Journal Article] A rapid and sensitive prenatal diagnosis of familial amyloidotic polyneuropathy (2009)
  • Author(s): Yamashita T, Ando Y, Ueda M, Okamoto S, Misumi Y, Nakamura M, Takashi O, Uchino M
  • Journal Title: Prenat Diagn Volume: 29 Pages: 930-933
  • Peer Reviewed
• [Presentation] 肝移植によらないアミロイドーシスの治療戦略,シンポジウム「アミロイドーシスとセルピノパチ-」 (2011)
  • Author(s): 安東由喜雄
  • Organizer: 第12回日本薬学会生物系薬学部会
  • Place of Presentation: 富山
  • Year and Date: 2011-06-18
• [Presentation] 家族性アミロイドポリニューロパチーの肝移植の効果とその問題点 (2011)
  • Author(s): 安東由喜雄
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] Familial amyloidotic polyneuropathy, recent news (2011)
  • Author(s): Ando Y
  • Organizer: 2011 Shanghai Jiao Tong UniversityInternational Neurological Diseases Symposium
  • Place of Presentation: Shanghai, China
  • Year and Date: 2011-04-22
• [Presentation] Recent news on amyloidosis. Academia Sinica Symposium (2010)
  • Author(s): Ando Y
  • Organizer: Taipei・Institute of Physics, Academi a Sinica
  • Place of Presentation: Taiwan
  • Year and Date: 2010-12-06
• [Presentation] Recent advances on hereditar y amyloidosis researches (2010)
  • Author(s): Ando Y
  • Organizer: 日中アミロイドーシス専家会議-同仁論壇2011
  • Place of Presentation: Tianjin・Teaching Hospital of Tianjin University of TCM, China
  • Year and Date: 2010-11-10
• [Presentation] Laboratory medicine and amyl oidosis (2010)
  • Author(s): Ando Y
  • Organizer: 日中アミロイドーシス専家会議-同仁論壇2011
  • Place of Presentation: Tianjin・T eaching Hospital of Tianjin University of TCM, China
  • Year and Date: 2010-11-10
• [Presentation] A new diagnostic method for h ereditary amyloidosis. Symposium on t he role of mass spectrometry in clini cal biochemistry (2010)
  • Author(s): Ando Y
  • Organizer: The 12^<th> Asian-Paci fic Congress of Clinical Biochemistry
  • Place of Presentation: Seoul・COEX, Korea
  • Year and Date: 2010-10-05
• [Presentation] 遺伝性アミロイドーシスの病態解析と治療 (2010)
  • Author(s): 安東由喜雄
  • Organizer: 第8回ヒトプロテオーム学会
  • Place of Presentation: 東京・東京ベイホテル東急
  • Year and Date: 2010-07-26
• [Presentation] Genotype and phenotype corre lation in FAP (2010)
  • Author(s): Ando Y
  • Organizer: The 12^<th> Symposium on amyloid and amyloidosis
  • Place of Presentation: Rome・Crowne Plaza Rome-St. Peter's Italy
  • Year and Date: 2010-04-21
• [Presentation] Combined genetic and proteomi c-based scerrning for hereditary amyl oidosis mutations Symposium on pathol ogy (2009)
  • Author(s): Ando Y
  • Organizer: The 25^<th> World Congress of Patho logy and Pathology update
  • Place of Presentation: Sydney, Australia
  • Year and Date: 20090313-15
• [Book] 今日の治療指針 (2012)
  • Author(s): 安東由喜雄
  • Total Pages: 801-802
  • Publisher: 医学書院、アミロイドニューロパチー
• [Book] 遺伝子・染色体検査業務、遺伝子分析学 (2011)
  • Author(s): 安東由喜雄
  • Total Pages: 237-240
  • Publisher: 克誠堂出版
• [Book] 家族性アミロイドポリニューロパチー、アミロイドーシス診療のすべて (2011)
  • Author(s): 安東由喜雄
  • Total Pages: 71-86
  • Publisher: 医歯薬出版
• [Book] 家族性アミロイドポリニューロパチー(FAP)の肝移植と新たな治療法の開発、Annual Review神経 (2010)
  • Author(s): 安東由喜雄
  • Total Pages: 310-317
  • Publisher: 中外医学社
• [Book] 家族性アミロイドポリニューロパチー(FAP)、今日の診断指針第6版 (2010)
  • Author(s): 安東由喜雄
  • Total Pages: 2091
  • Publisher: 医学書院
• [Book] New Therapeutic Approaches for Familial AmyloidoticPolyneuropathy(FAP) Recent Advances in Transthyretin Evolution, Structure and Biological Functions (2009)
  • Author(s): Ando Y, Nakamura M, Ueda M, Jono H
  • Total Pages: 215-238
  • Publisher: Springer
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/neurology/
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/diagnostic/index.htm
• [Patent(Industrial Property Rights)] アミロイド線維形成抑制剤及びその利用 (2010)
  • Inventor(s): 城野博史、安東由喜雄、有馬英俊、植田光晴、本山敬一
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Number: PCT出願、特願2009-155158
  • Filing Date: 2010-06-30