Generation and integration of new CNS neurons by in vivo directed conversion

描述(申请人提供)：本申请的目标是研究利用原位定向神经元转换(IDNC)将成人中枢神经系统现有的体内分化细胞--如星形胶质细胞--转化为具有功能和适当整合的神经元的可行性和要求。IDNC是一种新颖的方法，不同于干细胞方法。通过IDNC，利用多顺反子慢病毒载体或其他方式，将转录调节因子的混合物转导到成熟的中枢神经系统细胞，如星形胶质细胞。这些因素导致快速和定向的转化为独特的成熟神经元表型。这种定向转化挑战了分化的细胞表型固有稳定的基本原则--特别是在原位 中枢神经系统。定向转化潜在地克服了其他治疗细胞替代策略的一些固有困难，例如干细胞方法。直接转换现有单元可能对现有电路的一般架构的干扰最小。第二个也可能是更大的挑战是新转换的神经元与中枢神经系统局部电路的功能整合。这个问题将使用各种生理和光学成像方法来解决。

DESCRIPTION (provided by applicant): The goal of this application is to investigate the feasibility and requirements of converting existing in vivo, differentiated cells of the adult CNS - such as astroglia - into functional and appropriately integrated neurons, using in situ directed neuronal conversion (IDNC). IDNC is novel and distinct from stem cell approaches. With IDNC, a cocktail of transcription regulators is transduced into mature CNS cells, such as astroglia, using polycistronic lentiviral vectors or otherwise. These factors lead to a rapid and directed conversion into a distinct mature neuronal phenotype. Such directed conversion challenges the basic tenet that differentiated cell phenotypes are inherently stable - particularly in situ in the CNS. Directed conversion potentially overcomes some of the inherent difficulties with other therapeutic cell replacement strategies, such as stem cell approaches. Directly converting existing cells may be least intrusive on the general architecture of existing circuitry. A second and perhaps greater challenge is the functional integration of newly converted neurons into CNS local circuitry. This problem will be address using a variety of physiological and optical imaging approaches.