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Katherine A. High is a researcher at Howard Hughes Medical Institute (HHMI), a non-profit medical research organization with headquarters in Maryland, and Director of the Center for Cellular and Molecular Therapeutics at the Childen's Hospital of Philadelphia. Dr. High has dedicated her career to unraveling the molecular basis of haemophilia and she has been at the forefront of a movement to develop gene therapy as a treatment for the disease, a rare bleeding disorder which stems from a single inherited mutation in any of the several genes required for blood to clot properly. She has worked with dogs in which haemophilia occurs naturally and has demostrated that it can be successfully treated by inserting a normal clotting factor gene into the animals.

- What does the concept of gene therapy refer to? Has this concept changed in the past few years?

- Gene therapy is a new type of therapy in which the active agent is a nucleic acid (DNA or RNA) rather than a protein or a small molecule. There are several types of gene therapy: most current strategies use what is called gene addition therapy, that is, the therapy delivers a normal copy of a gene which is missing or defective in the recipient. A newer strategy is called genome editing; in this method, special enzymes are used to introduce a break in the DNA near the site of a mutation, then repair of the break is effected using a wild-type template (supplied as part of the therapy) and the cell’s own repair mechanisms.  In this newer strategy, the correction has to be carried out in the cell type that normally makes the protein, since only this cell type will express the gene properly once it has been corrected. 

- You've succeeded in curing dogs with haemophilia thanks to gene therapy. What results have you obtained from testing on humans with this disorder?

-We have accomplished these results using a gene addition strategy, and we have done it by putting the gene either into the liver (where clotting factors are normally made) or into the skeletal muscle. In humans, we have had an opportunity to try the identical strategy that resulted in cures in dogs in people with hemophilia. Once we reached a therapeutic dose, people achieved therapeutic levels of clotting factor, but unfortunately, after a period of about 10 weeks, this expression was lost. In research conducted over the past few years, we believe we have defined the reason for this, an immune response to the vector (gene delivery vehicle) used to deliver the gene encoding the clotting factor. A revised trial will test whether we are able to block this response and thus permit long-term expression of the clotting factor gene.
For the muscle approach, we have not yet had an opportunity to do a clinical study of the method that resulted in high level expression of clotting factors in dog muscle. An earlier study, in which vector was introduced by direct intramuscular injection, showed that the procedure was safe, but circulating levels of factor were too low to be therapeutic.

- Both the people suffering from incurable diseases and their families  have high hopes about what gene therapy can do. What would you tell them?

- I would tell them to be patient. Typically, new therapies take on the order of 20-30 years to develop. The first trials of human gene therapy were undertaken 15 years ago, and a few diseases have been successfully treated already. Perhaps most important, the field has developed a working list of the problems that need to be solved to extend gene therapy to a range of diseases, so we can expect more successes as these problems are solved. 

- What diseases is gene therapy especially helping to cure now?

- The most clear-cut examples of success are in the immunodeficiency disorders, particularly one called ADA-SCID. These are normally fatal if not treated, either by bone marrow transplantation or enzyme replacement. But gene therapy has cured approximately eight children with this fatal disorder, and they are now growing well and living at home on no medication. This is probably the most outstanding success.  Approximately 20 children with another type of immunodeficiency, X-linked SCID, have also been successfully treated, but four of these children went on to develop a serious complication, a syndrome resembling acute leukaemia, and one has died. Efforts have focused on modifying the vectors to prevent this type of complication from occurring in the future.   

- What are the main social and ethical challenges posed by gene therapy?

- Perhaps one of the biggest concerns is the risk of germline gene transfer, that is, the risk that DNA given to a recipient for therapeutic reasons would make its way to his or her germ cells (sperm or eggs) and be passed on to the next generation. The risk in that situation is that the extra DNA sequence might interfere with the pattern of precisely co-ordinated gene expression and repression that is required for normal embryonic and fetal development and thus result in a birth defect in the offspring of the recipient. So far, there has not been any evidence of this occurring, but continuing studies will be required to establish the safety of gene transfer.

- And what do you think will be the future of gene therapy?

- Gene therapy will become one of the treatment choices for people with genetic disease. It will ease the burden of genetic disease and permit a greater number of people to lead normal healthy lives.  People should remember though that the development of monoclonal antibodies as a therapy took approximately 30 years, and bone marrow transplantation similarly took years to become a standard therapeutic approach.  Thus it is important to recognize that development of completely new types of therapies can seem slow, but that each step brings the goal closer.

Interview: María Jesús Delgado
Photo: Antonio Zamora