Open AccessSleeping Beauty Transposon System is a Reliable Gene Delivery Tool for Hereditary Tyrosinaemia Type 1 Disease Gene Therapy: Size of the Foreign Gene Decides the Timing of Stable Integration into the Host Chromosomes
Author(s) -
Xuejun Pan,
Ma Zz,
Zhang Qj,
Li Fan,
Li Qh
Publication year - 2012
Publication title -
journal of international medical research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.421
H-Index - 57
eISSN - 1473-2300
pISSN - 0300-0605
DOI - 10.1177/030006051204000523
Subject(s) - gene , medicine , genetic enhancement , genetics , gene delivery , transposable element , disease , genome , biology , pathology
Objective: This study investigated compensation for loss of the fumaryl - aceto acetate hydrolase gene ( Fah) by gene therapy using the Sleeping Beauty transposon system (SBTS), in a hereditary tyrosinaemia type 1 (HT-1) mouse model (Fah -/- ).Methods: Twenty Fah -/- study mice, five wild-type positive controls and five Fah -/- negative controls were included. All Fah -/- mice received 2-(2- nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo - hexaedione (NTBC). Fah -/- study mice were randomly injected with one of two SBTSConstructs: Fah-SBTS (containing mouse Fah gene), or forkhead box M1b ( FOXM1B)- Fah-SBTS (containing mouse Fah and human FOXM1B genes). Firefly luciferase-SBTS was injected as a trace marker. NTBC treatment stopped after construct injection; Fah -/- negative controls were kept healthy with continued NTBC. Mice were weighed daily; the luciferase signal was monitored by in vivo bioluminescence, and Fah and FOXM1B gene expression were evaluated.Results: The Fah gene integrated into the mouse chromosomes within 1 week of Fah-SBTS injection (mice survived without NTBC thereafter) and within 1 month of FOXM1B-Fah-SBTS injection (mice lost weight dramatically and needed additional NTBC).Conclusion: The shorter Fah gene had an advantage over the longer FOXM1B-Fah gene for stable integration into the host mouse chromosomes.