Experimental therapy using double humanized mouse model for familial amyloidotic polyneuropathy.

• Project/Area Number: 24590404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: Kumamoto University
• Principal Investigator: LI Zhenghua 熊本大学, 生命資源研究支援センター, 特任助教 (80398239)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 分子遺伝学 / 家族性アミロイドポリニューロパチー / マウスモデル / CHF5074 / アミロイド

Outline of Final Research Achievements

We produced three strains of double humanized mice, Rbp4hRBP4: TtrhTTRVal/Val, Rbp4hRBP4: TtrhTTRVal/Met, Rbp4hRBP4: TtrhTTRMet/Met, by replacing mouse Rbp4 and Ttr gene with human RBP4 and normal or mutant TTR gene, respectively. Altough the serum hTTR levels were much lower than those in Tg(6.0-hTTRMet30) or Tg(6.0-hTTRMet30):Ttr-/-, similar amount of amyloid deposition was observed in alimentary tracts. In addition, amyloid deposition was observed in heart and sciatic nerve in Rbp4hRBP4: TtrhTTRVal/Val and Rbp4hRBP4: TtrhTTRMet/Met. Administration of CHF5074 to these mice resulted in increase of serum TTR by stabilizing TTR tetramers and in decrease of amyloid deposition in heart, stomach and sciatic nerve, suggesting that CHF5074 have a preventing effect on amyloid deposition.

Research Products

• [Journal Article] CHF5074 (CSP-1103) stabilizes human transthyretin in mice humanized at the transthyretin and retinol-binding protein loci. (2015)
  • Author(s): Mu, Yanshuang; Jin, Shoude; Shen, Jingling; Sugano, Aki; Takaoka, Yutaka; Qiang, Lixia; Imbimbo, Bruno P; Yamamura, Ken-Ichi; Li, Zhenghua
  • Journal Title: FEBS Letters Volume: 589 Issue: 7 Pages: 849-856
  • DOI: 10.1016/j.febslet.2015.02.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Improvement of retinal function and vitamin A availability in humanized mice at retinol-binding protein locus (2013)
  • Author(s): Li, Z., Mu, S., Shen, J., Araki, K. and Yamamura, K.
  • Organizer: 第３６回日本分子生物学会
  • Place of Presentation: 神戸国際会議場、神戸
• [Presentation] TtrおよびRbp遺伝子座のダブルヒト化による血中ヒトTTRの増加 (2012)
  • Author(s): 李 正花
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡（マリンメッセ福岡）
• [Presentation] Re-sequencing and refinement of genomic structure of six susceptibility regions to diabetes mellitus in a mice strain, MSM/Ms (2012)
  • Author(s): 要 匡
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡（マリンメッセ福岡）
• [Remarks] 熊本大学 生命資源研究支援センター
  • URL: http://irda-genetics.kuma-u.jp/
• [Remarks] 熊本大学 生命資源研究支援センター 疾患モデル分野
  • URL: http://irda-genetics.kuma-u.jp/research/r05.html