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Breakthrough Dividend: Chapter 16 - Gene Therapy

Genes contain the molecular "blueprints," encoded as DNA sequences, for producing the thousands of highly-specific proteins that make up our body. When a "misprint" (mutation) occurs, the resulting defective protein won't fold right, function correctly or, if a control element is botched, be produced at all. Clearly the best possible therapy would be to replace or supplement the defective genetic message with a normal, functional one. The techniques for doing this are just becoming available, and Israeli scientists are full participants in this effort, which has significant long-term potential.

The United States has recently approved several clinical trials including the use of retroviruses, which are one of nature's own delivery systems (vectors) for inserting foreign genes (in this case viral genes) into humans. In these trials, any harmful viral genes are removed (retroviruses are related to AIDS and cancer viruses) and replaced with the desired therapeutic genetic "message." Unfortunately, however, this delivery system is not very effective in the therapeutic mode. Hebrew University investigators have developed a much better vector from a much smaller, rather innocuous monkey virus, SV-40. They almost completely "gut" the virus, removing 95 percent of its DNA, but leave its delivery functions intact. Therapeutic genes are then added to create a 95 percent normal human, 5 percent SV-40, "pseudovirus." The human safety of SV-40 was inadvertently tested and proven in the 1950's when millions of Americans received SV-40 as a contaminant in polio vaccines, without harm. Not only is it safe, but the new Israeli pseudovirus is a much more efficient gene therapy vector than retroviruses and, an extra bonus, it is particularly good at transferring genes to the vital blood-forming and immunoactive cells of the bone marrow. The investigators have already transferred, with high efficiency, human -globin genes to human bone marrow cells in vitro.

The new vector could have immediate applications in cancer chemotherapy. Samples of the patient's bone marrow would be removed, imbued with multi-drug-resistance genes in vitro and returned to their place inside the patient, a simple and safe procedure. Then the patient could undergo even massive chemotherapy without the usual catastrophic effects on the sensitive cells of the bone marrow. The same procedure could be used to introduce normal glucocerebrosidase genes into the bone marrow of Gaucher disease patients and to introduce normal -globin genes into the bone marrow of -thalassemia patients (as mentioned, this gene transfer has already been successfully accomplished).

Further ahead, the Israeli pseudovirus could be directly delivered in aerosols to the epithelial cells of the lungs of patients with cystic fibrosis. In that case, the Israeli vector would deliver the gene for producing functioning membrane chloride channels (CFTR). The generality and versatility of this Hebrew University system suggest a particularly wide potential impact.

Although this field is extremely new, two Israeli startup companies are beginning to approach it from more traditional, but related fields. Applied Cell Care specializes in activated and modified human cell lines with therapeutic potential in treating AIDS and cancer, and in bone marrow transplantation. In this approach, often called "cell therapy," the patient's own genetic material is not directly modified; rather, he is provided with functioning externally-cultured cells with the desired genetic properties. Applied Cell Care is a private company with two overseas joint venture partners, Eriphyle (Holland) and Applied Immune Sciences (USA).

QBI Enterprises was established in 1993. Its technological "capital" includes a unique expression system that can be used to produce biologically-interesting proteins from mammalian cells in culture. One of their R&D targets is cellular and genetic therapies for blood diseases.

Given the embryonic state of the field, no obvious prior North Carolina counterparts could be identified.