Gene therapy for familial amyloidotic polyneuropathy (FAP)

家族性淀粉样变性多发性神经病 (FAP) 的基因治疗

• 批准号: 13670655
• 负责人: ANDO Yukio
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670655/
• 关键词: amyloidosis; familial amyloidotic polyneuropathy; gene therapy; transthyretin; oligonucleotides; athelocollagen; transgenic mice; liver; トランスジェニツクマウス; 家族性アミロイドポリニューロパチー; RNA; DNAキメラオリゴヌクレオチド; 点変異

Liver transplantation for familial amyloidotic polyneuropathy (FAP) revealed that replacement of the variant transthyretin (TTR) gene is effective for halting clinical symptoms of FAP. Thus, we need to develop a new treatment that prevents production of the variant TTR in the liver and retina. In this study, we used HepG2 cells to show in vitro conversion of the TTR gene by single-stranded oligonucleotides (SSOs), embedded in atelocollagen, designed to promote endogenous repair of genomic DNA. For the in vivo portion of the study, we used rabbit eyes and liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the murine TTR Val30Met gene. The rate of gene conversion was determined by real-time RCR combined with mutual-allele-specific amplification. Our results indicate that the rate of gene conversion was approximately 11%, 1%, and 9% of the total TTR gene in HepG2 cells, rabbit eyes, and liver from transgenic mice, respectively. Gene therapy via this method may therefore be a promising alternative to liver transplantation for treatment of FAP.

家族性淀粉样蛋白多神经病（FAP）的肝移植表明，变体经胸蛋白（TTR）基因的替代对于停止FAP的临床症状有效。因此，我们需要开发一种新的治疗方法，以防止肝脏和视网膜中变体TTR的产生。在这项研究中，我们使用HEPG2细胞显示了嵌入atelocollagen的单链寡核苷酸（SSO）对TTR基因的体外转化，旨在促进基因组DNA的内源性修复。对于研究的体内部分，我们使用了来自转基因小鼠的兔眼和肝脏，这些小鼠的内在野生型TTR基因被鼠TTR Val30met基因取代。基因转化率通过实时RCR与相互特异性扩增相结合确定。我们的结果表明，在HEPG2细胞，兔眼和转基因小鼠中，基因转化率分别约为总TTR基因的11％，1％和9％。因此，通过这种方法的基因治疗可能是用于治疗FAP的肝移植的有希望的替代方法。

项目成果

Ando Y: "New therapeutic approaches for familial amyloidotic polyneuropathy (FAP)"Amyloid. in press. (2003)

Ando Y：“家族性淀粉样变性多发性神经病 (FAP) 的新治疗方法”淀粉样蛋白。

Matsunaga N, Anan I, Forsgren S, Nagai R, Rosenberg P, Horiuchi S, Ando Y, and Suhr OB: "Advanced glycation end products (AGE) and the receptor for AGE are present in gastrointestinal tract of familial amyloidotic polyneuropathy patients but do not induce

Matsunaga N、Anan I、Forsgren S、Nagai R、Rosenberg P、Horiuchi S、Ando Y 和 Suhr OB：“晚期糖基化终末产物 (AGE) 和 AGE 受体存在于家族性淀粉样变性多发性神经病患者的胃肠道中，但

Ikeda S, Nakazato M, Ando Y, et al.: "Familial amyloidotic polyneuropathy in Japan : Clinical and genetic heterogeneity"Neurology. 58. 1001-1007 (2002)

Ikeda S、Nakazato M、Ando Y 等人：“日本家族性淀粉样变性多发性神经病：临床和遗传异质性”神经病学。

中村政明, 安東由喜雄, 内野誠: "家族性アミロイドポリニューロパチーの遺伝子治療"神経内科. 55. 525-529 (2001)

Masaaki Nakamura、Yukio Ando、Makoto Uchino：“家族性淀粉样多发性神经病的基因治疗”《神经病学》55. 525-529 (2001)。

Sakashita, N., Ando, Y., Jinnouchi, K., Yoshimatsu, M., Terazaki, H., Obayashi, K., Takeya, M.: "Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhage"Pathol. Int.. 51. 476-480 (2001

Sakashita, N.、Ando, Y.、Jinnouchi, K.、Yoshimatsu, M.、Terazaki, H.、Obayashi, K.、Takeya, M.：“家族性淀粉样变性多发性神经病 (ATTR Val30Met) 伴有广泛的脑淀粉样血管病和致命性