New Directions In Genetic Therapy Research.

ABSTRACT

Gene therapy involves transfer of normal healthy genes in patients to replace abnormal genes. In several human diseases such as cystic fibrosis, HIV infection, Duchenne's muscular dystrophy, Gaucher disease, arthritis, and cancer, gene therapy has been applied with encouraging success. Unfortunately, side effects are showing up, especially the response of host immune system. New directions in gene therapy research are being pursued to resolve these problems. An example of one such problem is the retrovirus gene delivery system. Since retroviruses grow only in dividing cells and integrated into the host genome in a random manner, the risk of tumor formatting increases. A denovirus can infect nondivinding cells but its titer is very low and it also provokes host immune system response. One the other hand, adeno-associated viruses (AAV) and Herpes simplex viruses, with deleted EI gene, which renders them replication defective can be directly injected into the patients or mixed with cells from the patients just prior to rein fusion. The AAV gene delivery system is (i) stable upon storage at room temperature, (ii) is not inactivated by components in the blood when directly injected into the patients and (iii) does not require specific cells for replication and very efficiently transfers genes into the host target cell DNA. The next vector of choice is cationic liposomes which are neither toxic nor causes cancer in cells. In cystic fibrosis, cationic liposomes have already been tried in the initial phase. The last technique which has been tried at least in 3 human trials is naked or particle meditated DNA injection. It suffers from low target ability and low efficiency effect,. Proposal of synthetic 25 the human chromosome has also been made. In this chromosomal vector not only the c DNA but also the regulatory sequences can also be introduced. In summary, the future of genetic therapy lies on the improvement of the delivery system of normal gene(s) into patients.