Research & Discovery
Gene therapy and protein therapy
by David Busch, Ph.D., M.D.
These two forms of therapy are commonly referred to when there is talk about finding a cure for XP.
XP patients may have a defect in any one of seven genes that normally provide the cell with information on how to make a protein that is important in repairing UV induced DNA damage. Gene therapy is a proposed method of changing the cell’s content of DNA so that the cell can make the missing protein, resulting in normal DNA repair and normal sun sensitivity. Protein therapy involves introducing the missing protein directly into the cell.
A form of protein therapy is in the process of undergoing clinical trials, while gene therapy for XP currently is science fiction but may become available within the next few years. Neither therapy will do anything to repair damage that has already occurred, such as freckling, still developing skin cancers, and neurological degeneration, although both could be helpful in minimizing future damage from future sun exposure. Here is a brief description of the techniques and their possible limitations.
Protein therapy is available to persons currently enrolled in Applied Genetics, Inc.’s T4N5 endonuclease study. In this study, XP patients are given a skin lotion containing a viral protein that simulates the action of the protein that XP patients lack. When the lotion is rubbed into the skin, the viral protein enters skin cells. It is hoped that this will result in the skin cells temporarily becoming more like normal cells, so that they repair UV damaged DNA better and there is less sunburning and skin cancer. The lotion method is analogous to giving insulin to diabetics; in that case, there is a problem with the body not making enough of an important protein (insulin), and the treatment is to give insulin injections to provide close to a normal level of protein.
It has not been proved that the lotion works, although it is likely to be useful; finding out if it works is the purpose of the clinical trials. The protein is not expected to persist in the skin indefinitely; it thus will be necessary to reapply it frequently, like a sunscreen. Thus, this really is intended as a treatment but not a cure. Protection is expected to exist only where the lotion is applied i.e., to the skin; other sun sensitive tissues such as eyes, nostrils, and front of mouth will not be protected if only the skin is treated; also, the protein does not enter the brain and thus should be of no value in preventing the development of neurological problems in the 20% (approximately) of XP patients with such problems.
A logical future development would be to instead administer a lotion containing the exact protein that the XP patient is missing, meaning that there would have to be seven different lotions for the seven different proteins defective in different XP patients with abnormal UV excision repair. This might work better than the viral protein. An advantage of the lotion is that if there are any undesired side effects, these should disappear immediately after use is discontinued.
Gene therapy may be attempted soon with XP patients in France. In this method, either an extra, normal copy of the defective gene is introduced into the cell so that there is an artificial normal gene in apition to the two abnormal genes the patient is born with; or else the abnormal genes are modified inside the cell so that they become normal genes. In either case, this means that the cell can now make the missing protein. Here are some of the many potential problems with gene therapy:
It is very difficult to put genes into enough cells in a live person to make a difference in the person’s health.
Even if the gene is introduced into the cell, it is possible that the cell may have difficulty using the gene to make the missing protein.
The cell may lose the normal gene over time, in which case the therapy may need to be repeated periodically.
It may be easier to treat some cells than other cells. It is likely that gene therapy will soon be available for the skin surface cells that produce most skin cancers, but it may take longer to invent effective therapy for the deeper skin cells that produce melanomas; and treating brain cells to prevent neurological problems may be much more difficult still.
The therapy, if successful, will cause the body to make a protein that the body previously lacked, which could result in allergic reactions such as are seen in kidney rejection. If the allergic reactions are severe enough, it could be necessary to take toxic and dangerous immunosuppressive drugs to inhibit the allergic reaction.
Depending on the method used, it is possible that the cellular DNA could be mutated extensively by the treatment, resulting in cancers from the therapy itself.
As more is learned about these techniques, it is likely that XP patients will benefit greatly from their use and lead much more normal, less restricted lives. However, it is important to realize that much still needs to be done in the way of developing and validating these techniques and in learning about their possible risks and limitations. XP patients should welcome the development of these techniques as a possible way of minimizing the consequences of their disease; but at the same time they must realize the limitiations of the techniques, and should be careful to learn of potential problems with the techniques and to weigh the potential risks against the possible benefits when considering their use, especially in the case of gene therapy.