Development of Novel Alternative Serotype Adenoviral Vectors for Gene Delivery in

描述（由申请人提供）：无数的研究已经检查了内耳基因治疗的潜力。在大多数情况下，他们关注的是腺病毒载体和进入耳蜗的传递。大多数研究强调观察由巨细胞病毒启动子驱动的标记基因的表达，并使用基于腺病毒血清型Ad5的第一代腺病毒构建物。腺病毒传递系统的主要优点是有效地将基因传递到大多数靶组织，易于合成和将腺病毒载体重定向到各种细胞类型的能力，以及在临床中的先进应用。目前腺病毒传递系统的主要缺点是基因传递不能靶向进入内耳的特定细胞，并且基于Ad5的载体在人群中具有很强的免疫识别能力。本研究将验证基于非Ad5血清型的腺病毒载体结合细胞类型特异性启动子可用于有效和特异性地将蛋白质传递到内耳的感觉细胞和支持细胞的假设。这些新的腺病毒载体将克服当前基于Ad5的系统的局限性。在SBIR第一阶段，我们将首先表征和选择新的腺病毒载体平台，有效地将基因传递到内耳，其次测试优选载体，在感觉细胞和使用特定启动子控制元件的支持细胞中选择性表达。有了这些结果和不断增加的基因组发现，可以设计和测试可能治疗内耳疾病的分子疗法。

DESCRIPTION (provided by applicant): Myriad studies have examined the potential of gene therapy in the inner ear. For the most part they have focused on adenoviral vectors and delivery into the cochlea. Most studies have emphasized looking at expression of marker genes driven by a CMV promoter and have used first generation adenoviral constructs based on the adenovirus serotype Ad5. The main advantages of the adenoviral delivery system are efficient gene delivery to most target tissues, the ease of synthesis and the ability to redirect adenoviral vectors to a variety of cell types and the advanced use of the vector system in the clinic. The main disadvantages of the current adenoviral delivery system is that gene delivery is not targeted for entry into specific cells in the inner ear and the Ad5 based vectors are strongly immunologically recognized in the human population. The proposed studies will test the hypothesis that adenoviral vectors based on non- Ad5 serotypes incorporating cell type specific promoters can be used to efficiently and specifically deliver proteins to the sensory cells and supporting cells of the inner ear. These new adenovirus vectors will overcome the limitations to the current Ad5 based system. During SBIR phase I we will first characterize and select novel adenoviral vector platforms that efficiently deliver genes to the inner ear and second test preferred vectors for selective expression in sensory cells and in supporting cells using specific promoter control elements. With these results in hand and the ever increasing genomic findings molecular therapeutics can be designed and tested that may treat inner ear disease. PUBLIC HEALTH RELEVANCE: This SBIR Phase 1 proposal tests the hypothesis that adenoviral vectors based on non- Ad5 serotypes incorporating cell type specific promoters can be used to efficiently and specifically deliver proteins to the sensory cells and supporting cells of the inner ear. These new adenovirus vectors will overcome the limitations to the current Ad5 based system. We will first characterize and select novel adenoviral vector platforms that efficiently deliver genes to the inner ear and second test preferred vectors for selective expression in sensory cells and in supporting cells using specific promoter control elements.