Pain treatment with xenogeneic cells transfected with drug inducible opiate gene

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We previously reported that xenogeneic cells, carrying the proopiomelanocortin (POMC) gene coding the precursor of the ACTH and 13-endorphin in a polymer capsule transplanted into the cerebrospinal fluid (CSF) space of rats, secrete b-endorphin and reduce their pain. However, the activities of transplanted cells were barely controlled by exogenous agents. The Tet-On system, one of the transcriptional transactivators, which requires certain tetracycline derivatives for specific DNA binding, has been developed and considered to be applicable for the control of the transplanted cells. The pUHD1O-3-POMC and pUHD172-lneo were co-transfected to Neuro2A, a mouse neuroblastoma cell line, named Neuro2A-POMC.Neuro2A cells carrying the doxycycline-inducible POMC gene expressed and secreted ACTH upon addition of the doxycycline in vitro in a dose-dependent manner. The encapsulated and transplanted cells in the CSF space of rats were stimulated by four intraperitoneal injections of doxycycline, and found to express ACTH after subsequence 36-hour incubation in vitro, depending on the amounts of injected doxycycline. These findings indicate that gene expression in xenogeneic cells in the CSF space can be manipulated by injection a relatively harmless drug, and suggest that our system is applicable to cell transplantation therapy in central nervous system diseases requiring well-controlled substance delivery.