AAV vector-meditated expression of HLA-G reduces injury-induced corneal vascularization, immune cell infiltration, and fibrosis.
AAV vector-meditated expression of HLA-G reduces injury-induced corneal vascularization, immune cell infiltration, and fibrosis.
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DOI：
10.1038/s41598-017-18002-9
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发表时间：
2017-12-19
影响因子：
4.6
通讯作者：
Gilger BC
中科院分区：
文献类型：
--
作者：
Hirsch ML;Conatser LM;Smith SM;Salmon JH;Wu J;Buglak NE;Davis R;Gilger BC
超过150万人由于遗传和/或环境因素而患有角膜血管化，损害视力并经常导致失明。目前角膜血管化的治疗在功效上是有限的，并且引起不期望的效果，具有讽刺意味的是，包括视力丧失。为了开发一种安全有效的角膜血管化治疗方法，利用人类白细胞抗原G（human leukocyte antigen G，HLA-G）诱导的天然免疫耐受机制，对腺相关病毒（adeno-associated virus，AAV）基因治疗角膜血管化进行了研究。在体外验证含有密码子优化的HLA-G1（跨膜）或HLA-G5（可溶性）同种型的自身互补AAV盒。然后，在角膜基质内注射后，在兔中测定使用嵌合AAV衣壳的AAV载体转导动力学。角膜创伤后一周，与对照治疗的眼睛相比，单次基质内注射scAAV 8 G9-optHLA-G1 + G5防止角膜血管化，抑制创伤诱导的T淋巴细胞浸润（其中一些是CD 8+），并显著减少肌成纤维细胞形成。生物分布分析表明，AAV载体仅在创伤诱导的角膜中持续存在;然而，观察到对载体衣壳的中和抗体应答不一致。收集的数据证明了scAAV 8 G9-optHLA-G安全有效地治疗角膜血管化和抑制纤维化的临床潜力，同时暗示了在眼表免疫和同种异体器官移植中的更广泛作用。
Over 1.5 million individuals suffer from cornea vascularization due to genetic and/or environmental factors, compromising visual acuity and often resulting in blindness. Current treatments of corneal vascularization are limited in efficacy and elicit undesirable effects including, ironically, vision loss. To develop a safe and effective therapy for corneal vascularization, adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by human leukocyte antigen G (HLA-G), was investigated. Self-complementary AAV cassettes containing codon optimized HLA-G1 (transmembrane) or HLA-G5 (soluble) isoforms were validated in vitro. Then, following a corneal intrastromal injection, AAV vector transduction kinetics, using a chimeric AAV capsid, were determined in rabbits. One week following corneal trauma, a single intrastromal injection of scAAV8G9-optHLA-G1 + G5 prevented corneal vascularization, inhibited trauma-induced T-lymphocyte infiltration (some of which were CD8+), and dramatically reduced myofibroblast formation compared to control treated eyes. Biodistribution analyses suggested AAV vectors persisted only in the trauma-induced corneas; however, a neutralizing antibody response to the vector capsid was observed inconsistently. The collective data demonstrate the clinical potential of scAAV8G9-optHLA-G to safely and effectively treat corneal vascularization and inhibit fibrosis while alluding to broader roles in ocular surface immunity and allogenic organ transplantation.
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影响因子：
3.7
作者：
Salganik M;Hirsch ML;Samulski RJ
通讯作者：
Samulski RJ
影响因子：
5.1
作者：
McCarty, DM;Monahan, PE;Samulski, RJ
通讯作者：
Samulski, RJ
影响因子：
5.1
作者：
McCarty, DM;Fu, H;Samulski, RJ
通讯作者：
Samulski, RJ
影响因子：
3.7
作者：
Hippert C;Ibanes S;Serratrice N;Court F;Malecaze F;Kremer EJ;Kalatzis V
通讯作者：
Kalatzis V
影响因子：
3.4
作者：
Mohan, RR;Hutcheon, AEK;Wilson, SE
通讯作者：
Wilson, SE