公开(公告)号：WO1997018319A1

公开(公告)日：1997-05-22

申请号：PCT/US1996017696

申请日：1996-11-01

Applicant: SOMATIX THERAPY CORPORATION

Inventor： SOMATIX THERAPY CORPORATION ,  LEFF, Stuart, E. ,  MANDEL, Ron

IPC: C12N15/86

CPC classification number: C12N9/0071 ,  A61K38/00 ,  A61K48/00 ,  C12N9/78

Abstract: The invention provides novel genetically modified host cells, vectors, and methods for the treatment of Parkinson's disease and other related disease conditions in which the dopamine production is deficient. The invention relates to the surprising discovery that coexpression of tyrosine hydroxylase and GTP cyclohydrolase enables host cells to produce elevated dopamine and L-DOPA without adding tetrahydrobiopterin and that the coexpression of GTP cyclohydrolase stabilizes tyrosine hydroxylase. One embodiment of the invention is genetically modified host cells containing heterologous polynucleotide sequences encoding and capable of expressing GTP cyclohydrolase and tyrosine hydroxylase. Other embodiments of the invention include genetic construction that contain and can simultaneously express polynucleotide sequences encoding a GTP cyclohydrolase and a tyrosine hydroxylase. The invention also provides methods of producing L-DOPA or dopamine using the host cells of the invention. The invention also provides methods of treating patients of Parkinson's disease or other diseases related to a dopamine production deficiency using the vectors and methods of the invention.

Abstract translation: 本发明提供了新型遗传修饰的宿主细胞，载体和用于治疗帕金森病和多巴胺生产缺乏的其他相关疾病状况的方法。 本发明涉及令​​人惊奇的发现：酪氨酸羟化酶和GTP环化水解酶的共表达能够使宿主细胞在不添加四氢生物蝶呤的情况下产生升高的多巴胺和L-DOPA，并且GTP环化水解酶的共表达稳定了酪氨酸羟化酶。 本发明的一个实施方案是含有编码并能够表达GTP环化水解酶和酪氨酸羟化酶的异源多核苷酸序列的遗传修饰宿主细胞。 本发明的其它实施方案包括含有并可以同时表达编码GTP环化水解酶和酪氨酸羟化酶的多核苷酸序列的遗传构建。 本发明还提供使用本发明的宿主细胞产生L-DOPA或多巴胺的方法。 本发明还提供了使用本发明的载体和方法治疗帕金森病患者或与多巴胺生产缺乏相关的其它疾病的方法。