Scruggs Brittni A, Berger Aubrey, Knudsen Travis, Kopp Francesca N, Hill Matthew, Trncic Emma, Anderson Kjersten, Iezzi Raymond, Marmorstein Alan D
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
Department of Pediatrics, Mayo Clinic, Rochester, MN, USA.
Sci Adv. 2025 Sep 5;11(36):eadv7922. doi: 10.1126/sciadv.adv7922.
Subretinal injection of adeno-associated virus (AAV) is generally more efficacious and less inflammatory than intravitreal injection for retinal gene therapy. However, adverse events (e.g., chorioretinal atrophy) have been reported in many patients receiving subretinal injection of Luxturna (voretigene neparvovec-rzyl) and experimental gene therapies. Subretinal injection confines transduction to the treated area. To address this, we manufactured high-concentration fibrin hydrogels encapsulating AAV2-green fluorescent protein (AAV2-). Gels had homogeneous AAV distribution, desired mechanical properties, and retained infectivity. Epiretinal placement of fibrin-AAV2- ( = 11) was compared to subretinal ( = 5) and intravitreal AAV2- injection ( = 3). The subretinal group exhibited inconsistent retinal pigment epithelium (RPE) transduction restricted to the injection region with severe atrophy in two cases. The intravitreal group had weak transduction and inflammation. In contrast, epiretinal hydrogels degraded within days and led to broad transduction of RPE without atrophy or inflammation. This technology could advance gene therapy for retinal degenerations and other ocular or systemic disorders.
对于视网膜基因治疗，视网膜下注射腺相关病毒（AAV）通常比玻璃体内注射更有效且炎症反应更小。然而，许多接受视网膜下注射Luxturna（voretigene neparvovec-rzyl）和实验性基因治疗的患者都报告了不良事件（如脉络膜视网膜萎缩）。视网膜下注射将转导限制在治疗区域。为了解决这个问题，我们制备了包裹AAV2-绿色荧光蛋白（AAV2-）的高浓度纤维蛋白水凝胶。凝胶中AAV分布均匀，具有所需的机械性能，并保留了感染性。将纤维蛋白-AAV2-（n = 11）置于视网膜前与视网膜下（n = 5）和玻璃体内注射AAV2-（n = 3）进行比较。视网膜下注射组在注射区域表现出不一致的视网膜色素上皮（RPE）转导，其中两例出现严重萎缩。玻璃体内注射组转导较弱且有炎症。相比之下，视网膜前水凝胶在数天内降解，并导致RPE广泛转导，且无萎缩或炎症。这项技术可能会推动视网膜变性及其他眼部或全身性疾病的基因治疗。
