Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects
Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects
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DOI：
10.1172/jci70462
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发表时间：
2014-01-01
影响因子：
15.9
通讯作者：
Gregory-Evans, Kevin
中科院分区：
文献类型：
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作者：
Gregory-Evans, Cheryl Y.;Wang, Xia;Gregory-Evans, Kevin
无虹膜是一种先天性进行性全眼疾病，伴有脑、嗅觉和胰腺异常，视力预后差。无虹膜的发展与无义突变有关，无义突变导致配对盒6 （PAX6）单倍不足。在这里，我们使用无虹膜小鼠模型来验证通过突变无关的无意义突变抑制策略操纵Pax6剂量可以限制眼睛进行性、产后损伤的假设。我们重点研究了无义抑制药物3[5-（2-氟苯基）-1,2,4-恶二唑-3-基]苯甲酸（去脂酸）和庆大霉素。值得注意的是，我们证明了无义抑制不仅可以抑制疾病进展，还可以稳定地逆转角膜、晶状体和视网膜畸形缺陷，并恢复视网膜的电和行为反应。通过局部应用药物制剂START（0.9%氯化钠，1%吐温80,1%阿图伦粉，1%羧甲基纤维素）获得了最成功的结果，该制剂旨在增强颗粒分散并增加悬浮液粘度。这些观察结果表明，眼睛在出生后仍保持着显著的发育可塑性，并对分子重塑保持敏感。此外，这些数据表明，其他与剂量敏感基因突变相关的神经发育异常可能通过无义抑制疗法可逆。
Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80,1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics.