Researchers at Stanford University in Palo Alto, California, have used a type of gene therapy to treat mice with a disease that mimics multiple sclerosis (MS). The treatment, which delayed the neural degeneration that is the hallmark of the disease, appears to have overcome one of the problems that has dogged most other forms of gene therapy: the difficulty of getting "healthy" genes into enough cells in the body to produce therapeutic results. In this case, a small number of modified cells seemed to do the trick. Although experts caution that it's a long way from mice to people, the experiments provide some hope that gene therapy may eventually prove useful in treating MS.
The Stanford researchers, led by immunologist Garry Fathman and virologist Gary Nolan, studied mice that can be induced to develop a condition known as experimental autoimmune encephalitis (EAE). In EAE, as with MS, immune cells attack a nerve cell protein called myelin, causing symptoms ranging from impaired vision to severe motor dysfunction and even death. The culprits are immune cells known as T helper-1, or TH1, which secrete an assortment of compounds called cytokines that promote the degradation of myelin through a process that is not well understood. In normal immune responses, a second type of helper cells, known as TH2, secrete another batch of cytokines, including one called interleukin-4 (IL-4) that turns off the cytokine release from TH1 cells. But in EAE and MS, TH2 cells never seem to make it to the disease site.
The Stanford researchers, who report their results in the current issue of the Journal of Experimental Medicine, used a clever trick to shut off this damaging immune response: They engineered TH1 cells to produce IL-4 instead of their normal cytokines. The researchers used a virus called a retrovirus to shuttle IL-4 genes--plus a "marker" to highlight when the genes are expressed--into a special line of mouse TH1 cells known to target myelin basic protein, the protein at the heart of EAE and MS. By looking for the marker, the researchers could pick out the cells making IL-4, and they then used standard cloning techniques to mass-produce them.
The researchers tested these cells on a batch of mice that had been injected with myelin basic protein, which triggers the autoimmune response and causes EAE symptoms to occur in about 2 weeks. After 10 days, the researchers injected some of these animals with the genetically engineered T cells. The treated mice developed much less severe symptoms and staved off illness for a longer period of time than did those that didn't receive the treatment.
The technique shows that a relatively small number of IL-4-producing cells can shut down or greatly reduce the autoimmune disease, says Fathman: "These cells put out the fire." Other researchers agree that the research shows early promise. "It shows that gene therapy can work if you know the cell biology that goes along with the disease," says Markus Grompe, a gene-therapy expert at the Oregon Health Sciences University, in Portland. Next, the Stanford group plans to engineer their retroviruses to transfer IL-4 genes directly into cells in live mice. If successful, it could eventually pave the way for gene-therapy tests of humans with MS.