In many cases, we would actually prefer to avoid treating the whole body if we can, partly to help limit the immune reactions going on, partly because treating fewer cells means less risk of rare side effects, and partly because in some cases there will be cell types in the body that actually need to not be expressing the gene we are trying to get into one specific organ or cell type. Even for genes that are expressed throughout the body, disease resulting from a defect is often specific to a few organs or even one specific cell type. So we would prefer to limit the gene therapy agent very specifically to just the cells we want to treat.
One way to limit which cells end up with the gene therapy agent involves the selection of the type of gene therapy vector. Some vectors will treat only actively growing cells, whereas others will treat cells in any state of growth. Some vectors are derived from viruses that already have some specificity in terms of which cells in the human body they prefer. Thus, if we were wanting to treat the eye, we would want to ask whether we could build a vector from a virus known to infect the eye. If we wanted to treat cystic fibrosis, we would want to build our vector from a virus that infects lung cells. Now, in most cases, we do not have the luxury of starting with viruses that show absolute specificity for just the cell we want to target, but we can again do a least a bit of limiting where our treatment goes, depending on the vector we select.
In theory, we can also make our gene therapy construct contain not only the gene we want to express but also a promoter region next to it that will control where the gene will be expressed. So far, in studies of transgenic animals, all too often a promoter region placed artificially into a cell does not grant a pattern of gene expression identical to the natural pattern usually directed by that promoter. The promoter will give very specific expression in just one cell type when present in its natural location on the chromosome but the transgenic version of the promoter will not give expression in all cells of that type, and it may also give some expression in other cells when present as part of an external construct added to the cells. This may be happening in part because the endogenous promoter (the one that was there in the first place) is affected by other regional things, such as the structure of the chromosome in the local region, or other sequences present at some distance from the promoter itself. Thus, although use of a promoter specific to a rod cell may allow us to get something expressed in some of the rod cells, we do not yet have a way to get completeness and specificity in targeting simply through use of the promoter.
One strategy for treating only the cells you want to treat is to remove the target cells from the body, treat them in culture, and then return them to the body once they are fixed. This can be done with blood cells if you just need to end up with some treated cells and do not need to fix every single cell. However, if you need to treat every cell in the liver, this approach will not work.
Another strategy for limiting delivery is to deliver into a localized region. The eye and brain are expected to be good targets for gene therapy because of the ability to treat without exposing the rest of the body. In treating the liver, some efforts to limit delivery involve injecting into vessels that feed directly into the liver, but this results in much gene therapy agent ending up in other parts of the body. In treating bone, the clever use of a gel to hold the gene therapy agent in a localized position seems to work. In addition, one of the biggest current problems with gene therapy in humans is the tendency of the body to develop an immune reaction to the gene therapy agent or even the treated cells themselves. The eye and the brain are different from the rest of the body in that the normal immune surveillance of most of the body does not extend to the eye and brain. Thus some kinds of immune reactions that eliminate the gene therapy agent or kill the treated cells elsewhere in the body can potentially be avoided for eye and brain. On the other hand, it is a well-known phenomenon that the eye can end up being attacked by the immune system if it attracts too much attention from the immune system, so testing of gene therapy approaches to the eye and the brain have to be explored very carefully.
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