The present review describes gene transfer into the brain using extraneuronal cells with an ex vivo approach. The mild immunological reactions in the central nervous system to grafts provided the rationale and empirical basis for brain-transplantation, to replace dying cells, of potential clinical relevance. Fetal human astrocytes were genetically engineered to express tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecolamines. These cells were also found to produce constitutively and secrete GDNF and interleukins. Therefore, these cells may prove as a drug-delivery system for the treatment of neurological degenerative conditions such as Parkinson's disease (PD). The field of neuronal reconstruction has reached a critical threshold and there is a need to evaluate the variables that will become critical as the field matures. One of the needs is to characterize the neurochemical alterations in the microenvironment in the context of grafted-host connectivity. This review discusses the functional effects of the pharmacologically-active construct, which consists of astrocytes producing L-DOPA and GDNF. The striatum in PD that lacks the dopaminergic projection from the substantia nigra metabolizes and releases dopamine differently from normal tissue and may react to different factors released by the grafted cells. Moreover, neurochemicals of the host tissue may effect grafted cells as well. An understanding of the way in which these neurochemicals are abnormal in PD and their role in the grafted brain is critical to the improvement of reconstructive strategies using cellular therapeutic strategies.
|Number of pages||27|
|Journal||Progress in Neurobiology|
|State||Published - Dec 1999|
Bibliographical noteFunding Information:
The authors thank Professor M. Weinstock-Rozin for her critical reading of the manuscript, Dr U. Herzberg for technical help with the immunohistochemistry, and acknowledge Drs C. Tornatore and E. Major for their part in the development of the SVG and SVG-TH cell lines. The studies presented in this review were supported in part by grants from the National Parkinson's Foundation USA and Bar-Ilan research Authority to G.Y.