DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice
DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice
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DOI：
10.1172/jci64833
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Naash, Muna I.
中科院分区：
文献类型：
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作者：
Han, Zongchao;Conley, Shannon M.;Naash, Muna I.
光感受器特异性翻转酶ABCA 4的突变与Stargardt病和目前缺乏治愈性疗法的许多其他形式的视网膜变性有关。基因置换是ABCA 4相关疾病的合理策略，特别是考虑到传统病毒介导的基因递送（如腺相关病毒（AAV）载体）目前的成功。然而，ABCA 4 cDNA的大尺寸（6.8kbp）阻碍了遗传治疗的发展。非病毒DNA纳米颗粒（NPs）可以容纳大的基因，不像传统的病毒载体，具有容量限制。我们利用优化的DNA NP技术将ABCA 4视网膜下递送至Abca 4缺陷型小鼠。我们检测到持续ABCA 4转基因表达长达8个月后注射，并发现显着的纠正功能和结构Stargardt表型，如改善恢复暗适应和减少脂褐质颗粒。这些数据表明，DNA纳米颗粒可能是一个很好的，临床相关的基因传递方法的基因太大，传统的病毒载体。
Mutations in the photoreceptor-specific flippase ABCA4 are associated with Stargardt disease and many other forms of retinal degeneration that currently lack curative therapies. Gene replacement is a logical strategy for ABCA4-associated disease, particularly given the current success of traditional viral-mediated gene delivery, such as with adeno-associated viral (AAV) vectors. However, the large size of the ABCA4 cDNA (6.8 kbp) has hampered progress in the development of genetic treatments. Nonviral DNA nanoparticles (NPs) can accommodate large genes, unlike traditional viral vectors, which have capacity limitations. We utilized an optimized DNA NP technology to subretinally deliver ABCA4 to Abca4-deficient mice. We detected persistent ABCA4 transgene expression for up to 8 months after injection and found marked correction of functional and structural Stargardt phenotypes, such as improved recovery of dark adaptation and reduced lipofuscin granules. These data suggest that DNA NPs may be an excellent, clinically relevant gene delivery approach for genes too large for traditional viral vectors.