Effective delivery of large genes to the retina by dual AAV vectors.
Effective delivery of large genes to the retina by dual AAV vectors.
复制标题
DOI：
10.1002/emmm.201302948
复制
发表时间：
2014-02
影响因子：
11.1
通讯作者：
Auricchio, Alberto
中科院分区：
文献类型：
--
作者：
Trapani, Ivana;Colella, Pasqualina;Sommella, Andrea;Iodice, Carolina;Cesi, Giulia;de Simone, Sonia;Marrocco, Elena;Rossi, Settimio;Giunti, Massimo;Palfi, Arpad;Farrar, Gwyneth J.;Polishchuk, Roman;Auricchio, Alberto
用腺相关病毒(AAV)载体进行视网膜基因治疗对人类是安全有效的。然而，由于AAV有限的货运能力，无法将其应用于遗传性视网膜疾病的治疗，原因是基因突变超过5kb，如Stargardt病(STGD)和Usher综合征IB型(USH1B)。以前基于“强制”将大基因包装到AAV衣壳中的方法可能不容易移植到临床上，因为产生了不同大小的基因组，这引发了安全问题。利用AAV的串联能力，我们产生了双AAV载体，它们通过剪接(反式剪接)、同源重组(重叠)或两者的组合(杂交)来重组一个大基因。我们发现，双重反式剪接和杂交载体有效地转导小鼠和猪光感受器的水平，尽管低于单一AAV的水平，但显著改善了STGD和USH1B小鼠模型的视网膜表型。因此，对于需要输送大基因的视网膜疾病的基因治疗，双AAV反式剪接或杂交载体是一种有吸引力的策略。
Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV's limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5 kb, like Stargardt's disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on ‘forced’ packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV's ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans-splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large genes.
登录
查看更多内容
影响因子：
12.4
作者：
Gargiulo, Annagiusi;Bonetti, Ciro;Surace, Enrico M.
通讯作者：
Surace, Enrico M.
影响因子：
--
作者：
Doria, Monica;Ferrara, Antonella;Auricchio, Alberto
通讯作者：
Auricchio, Alberto
影响因子：
5.4
作者：
Allocca, Mariacarmela;Mussolino, Claudio;Auricchio, Alberto
通讯作者：
Auricchio, Alberto
影响因子：
3.7
作者：
Dong X;Foteinou PT;Calvano SE;Lowry SF;Androulakis IP
通讯作者：
Androulakis IP
影响因子：
4.4
作者：
Gibbs D;Diemer T;Khanobdee K;Hu J;Bok D;Williams DS
通讯作者：
Williams DS