Report from the American Society for Gene Therapy; June 14, 1999,by Karen Hopkin

"... exercise, when combined with gene or cell therapy, should allow newborn therapeutic neurons to proliferate and survive."
     Even in the aging brain, some cells never grow up. Over the past several years, Gage and other researchers have shown that in rats, mice, monkeys, and man, neurons continue to be born even after the animals are no longer spring chickens. The progenitor cells that spawn these neurons reside in two brain regions in particular--the hippocampus, which controls learning and memory, and the subventricular zone, which in the embryo supplies neurons to the developing cortex. These progenitor cells divide and their offspring migrate to other brain regions, where they form neurons with established connections or become the supportive glial cells.

     The real fun, for researchers like Gage, is figuring out how the cells differentiate--and how their fate can be altered to suit the scientists' needs. If the progenitor cells could be tricked into producing dopamine, for example, they might prove useful for treating Parkinson's disease. Or they might in other ways be persuaded to help patch up a severed spinal cord.

     In fact these fantasies may well be within the realm of possibility. Gage, for one, finds that progenitor cells harvested from either the hippocampus or the subventricular zone can respond to local growth-factor cues when transplanted to just about anywhere in the brain, generating healthy new neurons--even to the spinal cord, which is normally thought to be an area fairly resistant to self-repair. Put progenitor cells in the eye, says Gage, and they can even turn into something resembling a photoreceptor.

     What's more, Gage and his colleagues have shown that by providing these progenitor cells with particular growth factors or neurotrophic factors, they can begin to direct how the cells perform. Most of these studies involve using retroviruses to stably introduce genes into the progenitor cells--or into cells they might come in contact with. For example, Gage can custom-build neurons that produce dopamine simply by transfecting progenitor cells with the gene for Nurr1, a transcription factor important for the development of dopaminergic neurons. These cells then switch on their gene for tyrosine hydroxylase--an enzyme key in the production of dopamine.

     Even in the spinal cord neurotrophic factors can kick start the proliferation of new neurons. Gage has armed ordinary fibroblasts with the gene for neurotrophin-3. And when those cells are placed in an injured spinal cord, they stimulate the birth not only of neurons but of the oligodendrocytes that produce the fatty myelin that sheaths their axons.

     Perhaps most exciting development is that Gage is hoping to use behavioral therapy to regulate the proliferation and survival of new neurons. Years ago, he and his colleagues demonstrated that mice raised in a stimulating environment had more new neurons in the hippocampus. Now he has found that just letting the rodents exercise produces the same effect. When mice jog four to six miles a day on their running wheels--an activity they engage in quite happily--the animals show a 60 percent increase in the number of new neurons. Such exercise, when combined with gene or cell therapy, should allow newborn therapeutic neurons to proliferate and survive.