CHALLENGES IN GENE THERAPY
Gene therapy is not a new field; it has been evolving for decades. Despite the best efforts of researchers around the world, however, gene therapy has seen only limited success. Why?
The answer is that gene therapy poses one of the greatest technical challenges in modern medicine. It is very hard to introduce new genes into cells of the body. Let's look at some of the main technical issues in gene therapy.
Gene delivery and activation
Gene therapy will work only if we can deliver a normal gene to a large number of cells - say, several million - in a tissue. And they have to be the correct cells, in the correct tissue. Once the gene reaches its destination, it must be activated, or turned on to produce the protein encoded by the gene. Gene delivery and activation are the biggest obstacles facing gene therapy researchers. Tools of the Trade highlights some of the most common methods for addressing these challenges.
Introducing changes into the germline
Targeting a gene to the correct cells is crucial to the success of any gene therapy treatment. Just as important, though, is making sure that the gene is not incorporated into the wrong cells. Delivering a gene to the wrong tissue would be inefficient and could cause health problems for the patient.
For example, improper targeting could incorporate the therapeutic gene into a patient's germline, or reproductive cells, which ultimately produce sperm and eggs. Should this happen, the patient would pass the introduced gene on to his or her offspring. The consequences would vary, depending on the type of gene introduced.
Our immune systems are very good at fighting off intruders such as bacteria, viruses and other biological substances. Gene delivery vectors must be able to escape the body's natural surveillance systems. Failure to do so can cause serious illness or even death.
The story of Jesse Gelsinger illustrates this challenge well. Gelsinger, who had a rare liver
disorder, participated in a 1999 gene therapy trial at the University of Pennsylvania. He died of
complications from an inflammatory response shortly after receiving a dose of experimental
adenovirus vector. His death halted all gene therapy trials in the United States for a time,
sparking a much-needed discussion on how best to regulate experimental trials and report health
problems in volunteer patients.
Disrupting important genes in target cells
The best gene therapy is the one that lasts. Ideally, we would want a gene that is introduced into a group of cells to remain there and continue working.
For this to happen, the newly introduced gene must become a permanent part of each cell's genome, usually by integrating, or "stitching" itself, into the cell's existing DNA. But what happens if the gene stitches itself into an inappropriate location, disrupting another gene?
This happened recently in a gene therapy trial to treat several children with X-linked Severe Combined Immune Deficiency (SCID). People with this disorder have virtually no immune protection against bacteria and viruses. To escape infections and illnesses, they must live in a completely germ-free environment.
In the late 1990s, researchers tested a gene therapy treatment that would restore the function of a crucial gene, gamma c, to cells of the immune system. This treatment appeared very successful, restoring immune function to most of the children who received it.
But later, two of these children developed leukemia. Researchers found that the leukemia occurred because the newly transferred gamma c gene had stitched itself into the wrong place, interrupting the function of a gene that normally helps regulate the rate at which cells divide. As a result, the cells began to divide out of control, causing the blood cancer leukemia.
Although doctors have treated the children successfully with chemotherapy, the fact that they developed leukemia during treatment raises another important safety-related issue that gene therapy researchers must address.
Supported by a Science Education Partnership
Award (SEPA) [No. 1 R25 RR16291-01] from the National Center for Research Resources, a component of the
National Institutes of Health, Department of Health and Human Services. The contents provided
here are solely the responsibility of the authors and do not necessarily represent the official
views of NCRR or NIH.
For more information about Jesse Gelsinger and Severe Combined Immune Deficiency, see Additional Resources.