Gene Therapy
Dr. Shy enthusiastic about the future – much work to be done (December 1997)
Linda here – I've had several calls from readers asking me about the state of genetic research to date. Most referred to the work of the team at the neuromuscular clinic at Wayne State University School of Medicine in Detroit, Michigan headed by Dr. Michael Shy. I asked Dr. Shy, associate professor of neurology and molecular medicine, to comment and he writes: "We were pleased to hear from you that people were excited bout our efforts to develop gene therapy for treatment of CMT. While we are excited about preliminary results we have obtained using pieces of adenovirus to introduce genes into mice, there are many challenges that must be overcome before this strategy can be used in patients. I'll briefly list some of these below.

"First, the exact gene or genes to introduce into Schwann cells in CMT1A, or in any form of CMT, remains unknown. Simply introducing more PMP22, the gene responsible for CMT1A, into Schwann cells will not resolve the problem because there is already too much PMP22 in the cells. This is what causes the disease. If the levels of PMP22 are reduced in the cell, it must be done is such a way that the dose doesn't fall too low. If there is too little PMP22 patients develop hereditary neuropathy with liability to pressure palsies (HNPP).

"Second, in our experiments, we introduce genes into nerves by directly injecting recombinant viruses containing these genes into the Schwann cells or myelin forming cells of the nerve. In these injections, we introduce our genes into some but not all Schwann cells. A more efficient delivery system in which all, or at least many more, Schwann cells receive the transplanted genes will have to be developed before this approach can be practical in patients.

"Third, the pieces of adenovirus (a common respiratory virus) that we use to introduce genes into Schwann cells permit the virus to infect many cell types, not just Schwann cells. We need to develop the technology to only put the genes into the Schwann cells before this approach will be ready for use in patiens.

"Fourth, the genes we introduce into Schwann cells are only expressed for a short time because they are cleared by the immune system. We need to develop a safe methodology to suppress a patient's immune system without exposing the patient to risks of infections and other diseases because of the suppressed immune system.

"I make these points not to sound pessimistic about the future. I firmly believe that these obstacles will eventually be overcome. Gene therapy will ultimately be used, I believe, not only to treat CMT but to treat many other genetic diseases as well. These challenges are the barriers that must be overcome to make gene therapy a reality.

"To keep all of this in perspective, I would remind your readers that the specific genetic abnormality that causes CMT1A has only been known since 1991. The field of gene therapy, with attempts to introduce genes into mammalian cells with viral vectors, is only about five years old itself. Advances in gene therapy will occur but the technology is not yet adequate to treat CMT or any other disease at the present time.

"We hope that people will not become disillusioned with gene therapy because obstacles exist. Rather we hope they will share our enthusiasm and belief that developing treatments to cure genetic diseases is the next great challenge for investigators studying diseases like CMT."