Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible?

The elucidation of the genetic defect in patients with Huntington's disease (HD) has allowed for the detection of individuals at risk for HD prior to the onset of symptoms. Thus "neuroprotection strategies" aimed at preventing the neuropathological and behavioral sequelae of this disease might be powerful therapeutically since they could be introduced to healthy patients before the initiation of a massive degenerative cascade principally localized to the striatum. A variety of trophic factors potently protect vulnerable striatal neurons in animal models of HD. A number of experimental variables are critical in determining the success of trophic factors in animal models. In this regard, the method of trophic factor delivery may be crucial, as delivery via genetically modified cells often produces greater and more widespread effects on striatal neurons than infusions of that same factor. The mechanisms by which cellularly delivered trophic factors forestall degeneration and prevent behavioral deficits are complex and often appear to be unrelated to the trophic factor binding to its cognate receptor. In this regard, cells genetically modified to secrete nerve growth factor (NGF) or ciliary neurotrophic factor (CNTF) protect degenerating striatal neurons which do not express either NGF or CNTF receptors. This review will discuss some of the non-receptor-based events that might underlie these effects and present the hypothesis that cellular delivery of certain trophic factors using genetically modified cells may be ready for clinical testing in HD patients. Copyright 1999 Academic Press.