Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179.
Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179.
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DOI：
10.1038/ncomms7006
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发表时间：
2015-01-23
影响因子：
16.6
通讯作者：
Ali, Robin R.
中科院分区：
文献类型：
--
作者：
Nishiguchi, Koji M.;Carvalho, Livia S.;Rizzi, Matteo;Powell, Kate;Holthaus, Sophia-Martha Kleine;Azam, Selina A.;Duran, Yanai;Ribeiro, Joana;Luhmann, Ulrich F. O.;Bainbridge, James W. B.;Smith, Alexander J.;Ali, Robin R.
Pde6b基因突变的rd1小鼠是第一个被鉴定出患有视网膜变性的小鼠品系。然而，AAV介导的rd1小鼠的基因补充仅导致光感受器的结构保留和光感受器介导的a波的恢复，但不恢复双极细胞介导的b波。在这里，我们发现Gpr179的突变阻止了rd1小鼠视力的完全恢复。与C57BL6小鼠回交rd1揭示了小鼠亚组中完全缺乏b波，与常染色体隐性孟德尔遗传模式一致。我们确定了Gpr179基因的突变，该基因编码定位于ON双极细胞树突的G蛋白偶联受体。没有Gpr179突变的rd1小鼠的基因替换成功地恢复了光感受器和双极细胞的功能，并维持了长达13个月。我们的发现可以解释以前在rd1小鼠中基因治疗尝试的失败，我们建议在未来涉及rd1小鼠的研究中应考虑Grp179突变状态。 rd1小鼠是研究视网膜变性最广泛使用的模型。在这里，作者在这些小鼠中发现了一种广泛分布的突变，这可能解释了以前基因治疗方法的失败，并表明在没有这种突变的rd1小鼠中长期恢复视力是可能的。
The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice. The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.
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影响因子：
3.7
作者：
Luhmann UF;Lange CA;Robbie S;Munro PM;Cowing JA;Armer HE;Luong V;Carvalho LS;MacLaren RE;Fitzke FW;Bainbridge JW;Ali RR
通讯作者：
Ali RR
影响因子：
3.7
作者：
Chu CJ;Herrmann P;Carvalho LS;Liyanage SE;Bainbridge JW;Ali RR;Dick AD;Luhmann UF
通讯作者：
Luhmann UF
影响因子：
3.7
作者：
Kranz K;Paquet-Durand F;Weiler R;Janssen-Bienhold U;Dedek K
通讯作者：
Dedek K
影响因子：
5.1
作者：
Petrulis, JR;Perdew, GH
通讯作者：
Perdew, GH
影响因子：
4.4
作者：
Allocca, Mariacarmela;Manfredi, Anna;Auricchio, Alberto
通讯作者：
Auricchio, Alberto