Gene Targeting and Regulation for Neurological Disease

描述（由申请人提供）： 利用基因治疗载体的治疗进展最近在许多神经系统疾病的临床前研究中显示出巨大的希望。然而，中枢神经系统为成功的基因治疗方法的开发和这种治疗方式向临床的推进提出了独特的挑战。为了加速基因治疗在临床上的应用，还有一些问题有待进一步研究和解决。在基因治疗中引起重大关注的一个主要问题是长期安全性。需要进一步研究的第二个问题是开发针对大脑患病区域的有效递送策略。第三，需要开发治疗性转基因的长期和受控表达的有效方法。评估拟议方法学进展的有效性和安全性需要在神经退行性疾病的动物模型中进行临床前试验。我们最近发现腺相关载体（AAV）具有在神经系统内逆行转运的独特性质，并且我们已经利用这一发现将治疗性转基因有效地递送到大脑的不同区域。此外，我们最近设计了一种新的可调控的AAV载体系统，允许控制转基因表达。该系统的新奇允许基因被一个配体快速打开，并被第二个不同的配体快速关闭。在这个项目中，我们建议开发有效的，有针对性的基因传递到神经系统和测试可再循环的AAV载体系统在体外和体内的应用。我们将评估该系统有效递送治疗性转基因的能力，这些转基因将预防或减缓神经退行性疾病中发生的细胞死亡，并利用这种新方法来确定干预疾病进展的治疗窗口。

DESCRIPTION (provided by applicant): Therapeutic advances utilizing gene therapy vectors have recently shown great promise in a number of pre-clinical studies of neurological disorders. The central nervous system, however, presents unique challenges for the development of successful gene therapy approaches and advancement of this therapeutic modality to the clinic. To accelerate gene therapy applications into the clinic, several issues remain to be further examined and resolved. One major issue that has raised significant concern in gene therapy is long-term safety. A second issue that requires further research is the development of efficient delivery strategies to target diseased regions of the brain. Thirdly, effective methods for both long-term and controlled expression of therapeutic transgenes need to be developed. Assessment of the efficacy and safety of proposed methodological advances would require pre-clinical testing in animal models of neurodegenerative disorders. We have recently discovered that adeno-associated vectors (AAV) have the unique property of retrograde transport within the nervous system and we have utilized this finding to efficiently deliver therapeutic transgenes to distinct regions of the brain. Furthermore, we have recently engineered a novel regulatable AAV vector system that allows control of transgene expression. The novelty of the system allows genes to be rapidly turned on with one ligand and rapidly turned off by a second, different ligand. In this project, we propose to develop efficient, targeted gene delivery to the nervous system and test the recrulatable AAV vector system for in vitro and in vivo applications. We will assess the ability of this system to efficiently deliver therapeutic transgenes that will prevent or slow cell death occurring in neurodegenerative diseases, and utilize this new methodology to determine therapeutic windows for intervening in disease progression.