From the presentation given at the National Coalition for PKU and Allied Disorders Metabolic Conference in Ohio in May 2001.

Dr. Dean Danner, Vice Chair in the Dept. of Genetics, Emory University, presented an interesting talk on Gene Therapy. He did an excellent job explaining an extremely complex subject in a way we could understand. He addressed four questions about gene therapy:

  1. What is the reason for hope in gene therapy?
  2. Why is it so popular with inborn errors of metabolism?
  3. What are the problems?
  4. Where are we now in reaching the goal of gene therapy?

Currently, the hope of gene therapy involves a threefold approach:

  1. Add a good gene and allow the body to make the necessary product - one not being made by the mutant gene [such as is the case with MSUD].
  2. Add a gene to stimulate the immune system.
  3. Add a gene to kill cancer cells.

The ultimate goal is to eventually replace a bad gene or to repair it completely.

The fact that inborn errors of metabolism involve only single gene defects means that replacement would offer a permanent cure and NO MORE DIET! Correction has been demonstrated in cultured cells for many single gene traits. There has been some success in rodents and some recent positive results in experiments with lower primates. But that is a long way from making it work in humans.

Certainly, it would be a mistake to minimize the problems that we face in making gene therapy feasible for humans. The problems include the health of the recipient and the questions of timing (i.e. do you treat in utero, in the new-born period, or later?). Each period for treatment presents its own set of problems. Only somatic (mostly non-dividing) cells can be treated, not embryonic stem cells. Can specific tissues be targeted? MSUD genes are expressed throughout the body; how can expression be regulated? How do we insure that the gene, once introduced, will continue to work; and what is the immune response of the body going to be to a new protein introduced into it? The mutant gene will still be present - how will that affect the functioning of the new gene? What will be the method of delivering the new gene into the system? The ever present bottom line is, of course, who is going to pay for the research needed and for the implementation of treatment when, and if, it becomes feasible?

The ideal vector for gene delivery into the body:

  1. Should be easy to produce.
  2. Should produce no immune response in the patient.
  3. Should ensure that the product is continually produced after delivery.
  4. Must ensure that it is expressed in the desired tissue (meaning you only want it to work where you want it to work).
  5. Cannot restrict the size of the delivered gene.
  6. Must be able to enter dividing and non-dividing cells.
  7. Must be controlled expression of the gene.

How do you go about putting genes into cells? So far, researchers have used physical means such as electroporation, microinjection and liposomes to introduce the gene. They are now experimenting with viruses.

The non-viral system for gene therapy, naked DNA and liposomes, has the advantage of being inexpensive (relative to other systems), easy to produce, not toxic or immunogenic (having the ability to stimulate the formation of antibodies). However, on the downside, this system is inefficient because the effects don't last, and the procedure has to be repeated again and again.

Using viruses as a delivery system has the advantage of being easy to deliver into the cells and can produce the gene in many cells. Again, the flip side: gene size is limited; some viruses will only infect dividing cells; sometimes hard to produce in large amounts; and they do produce, to varying degrees, an immune system response in the patient.

Several different viruses are being studied for possible use in this way - including the virus which causes the common cold. Each virus has advantages and disadvantages which must be overcome. Some only work on non-dividing cells, some are highly toxic, some have a very short life. The ones that seem to have the greatest advantages, also seem to have the most disadvantages. For instance, the Herpes Simplex virus works in dividing or non-dividing cells and neurons, but is highly toxic. The cold virus also works on dividing and non-dividing cells but has a very short life and is antigenic (capable of causing the production of an antibody).

The history of gene therapy (from 1980 to 2000) is one of limited successes and spectacular failures. Currently, there are more than 400 approved clinical trials ongoing worldwide. However, less than 15% of these are for single gene traits, the majority being in the area of cancer treatment and cardiovascular disease.