脑动静脉畸形 (bAVM) 引起的鼻出血和颅内出血是遗传性出血性毛细血管扩张症 (HHT) 患者最具破坏性的症状之一。所有可用的管理都有局限性。我们发现，使用腺相关病毒载体 (AAV9-sFLT1) 静脉内 (i.v.) 递送可溶性猫麦克唐纳肉瘤 (FMS) 相关酪氨酸激酶 1 可降低内皮糖蛋白缺陷小鼠的 bAVM 严重程度。然而，在年轻小鼠中观察到轻微的肝脏炎症和生长停滞。为了确定能够以最佳转导曲线最好地转导脑和鼻组织的 AAV 变体和递送方法，我们将 3 个工程 AAV 衣壳（AAV.cc47、AAV.cc84 和 AAV1RX）与 AAV9 进行了比较。单链 CBA 启动子驱动的 tdTomato 转基因被包装在这些衣壳中并静脉注射。或鼻内 (i.n) 给野生型小鼠。 CMV 启动子驱动的 Alk1 转基因被包装到 AAV.cc84 中，并通过静脉注射递送至 PdgfbiCre;Alk1f/f 小鼠。随后进行 bAVM 诱导。对器官中的转导细胞、血管密度、bAVM 中的异常血管和肝脏炎症进行组织学分析。通过酶法测量肝和肾功能。与其他病毒载体相比，AAV.cc84，静脉注射后。递送，转导高比例的脑内皮细胞（EC）和少量肝细胞；而在 i.n. 之后递送过程中，AAV.cc84 转导了大脑中的 EC 和血管周围细胞，以及鼻子中的 EC、上皮细胞和肌肉，并且肝细胞转导最少。未检测到肝或肾功能的变化。通过静脉注射 AAV.cc84-Alk1 的递送PdgfbiCre;Alk1f/f 小鼠可降低 bAVM 严重程度。总之，我们认为 AAV.cc84-Alk1 是开发 HHT 患者基因治疗的有希望的候选者。© 2024。作者获得 Springer Science Business Media, LLC（Springer Nature 旗下公司）的独家许可。

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous (i.v.) delivery of soluble Feline McDonough Sarcoma (FMS)-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84, and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1f/f mice through i.v. followed by bAVM induction. Transduced cells in organs, vessel density, abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain endothelial cells (ECs) and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. The delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.