Gene therapy in golden retriever muscular dystrophy model

金毛犬肌营养不良模型的基因治疗 本项目将以DMD犬模型（GRMD）为研究对象，探讨血管介导的基因传递， AAV载体进入四肢并最终进入全身。具体目标1旨在比较区域 动脉和静脉方法在肢体中的基因递送效率。带压动脉输送和/或 在早期的研究中，一些实验室对血管扩张器进行了研究。但最近的研究转向了 加压静脉注射方法。然而，最新的一份报告再次恢复了动脉方法， 而不使用任何额外的压力和药物。这些方法各有利弊，但 从来没有并排比较过。在目标1中，我们提出比较和优化区域AAV载体 狗四肢的分娩方法。特异性目的2旨在检查系统性基因递送效率， 在狗中的AAV 8和AAV 9。以前，我们和其他人已经表明，新的AAV血清型可以实现 在小鼠和仓鼠中通过简单静脉内注射进行全身基因递送。在目标2中，我们计划探索 AAV 8和AAV 9两者用于狗中的全身性基因递送。我们还将研究任何新的AAV载体 由Project 2提供。

Gene therapy in golden retriever muscular dystrophy model This project will focus on the DMD dog model (GRMD) to investigate blood-vessel-mediated gene delivery of AAV vectors into the limbs and eventually the wholedody. Specific Aim 1 is designed to compare regional gene delivery efficiency of arterial and venous methods in the limbs. Arterial delivery with pressure and/or with vessel dilators was investigated in early studies by a few labs. But more recent studies have switched to the pressurized intravenous delivery methods. However, a latest report revived the arterial method again, but without the use of any additional pressure and drugs. These methods have their pros and cons, but are never compared side-by-side. In Aim 1 we propose to compare and optimize the regional AAV vector delivery methods in dog limbs. Specific Aim 2 is designed to examine systemic gene delivery efficiency of AAV8 and AAV9 in dogs. Previously we and others have shown that new serotypes of AAV can achieve wholebody gene delivery by simple intravenous injection in mice and hamsters. In Aim 2, we plan to explore both AAV8 and AAV9 for systemic gene delivery in the dogs. We will also examine any novel AAV vectors yielded by Project 2.