Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations.
Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations.
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DOI：
10.1038/cddiscovery.2016.40
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发表时间：
2016
影响因子：
7
通讯作者：
Paquet-Durand F
中科院分区：
文献类型：
--
作者：
Jiao K;Sahaboglu A;Zrenner E;Ueffing M;Ekström PA;Paquet-Durand F
视网膜色素变性（RP）是一种遗传性致盲疾病，由多种不同的突变引起，这些突变影响视网膜感光细胞的功能和存活。到目前为止，既没有有效的治疗方法，也没有治愈方法。我们以前已经表明，聚（ADP-核糖）聚合酶（PARP）作为光感受器细胞死亡的共同和关键分母，使其成为未来治疗干预的潜在靶点。RP引起的突变的一个重要部分影响视杆细胞磷酸二酯酶6A（PDE 6A）亚基的基因，但目前还不知道他们是否都从事相同的死亡途径。在与人类RP患者匹配的小鼠模型中分析三种纯合点突变（Pde 6a R562 W、D 670 G和V685 M）和一种复合杂合Pde 6aV 685 M/R562 W突变，我们证明了PARP的过度激活，其与光感受器变性的进展及时相关。在用PARP选择性抑制剂PJ 34处理的器官型视网膜外植体培养物中，使用不同的处理时间点和持续时间，证实了PARP活性在神经变性过程中的因果关系。值得注意的是，PARP抑制的神经保护功效与遗传诱导的损伤的强度呈负相关，D 670 G突变体显示出最佳的治疗效果。我们的研究结果突出了PARP作为PDE 6A突变引起的RP神经保护干预的靶点，并且是RP个性化，基因型匹配治疗开发的首次尝试。此外，对于每种不同的突变情况，我们的工作确定了最佳治疗方案的机会窗口，以供进一步的体内实验和可能的临床研究。
Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6aV685M/R562W mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies.