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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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October 14, 2002

Gene Therapy Decisions

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Posted by Derek

There's been a flurry of news about gene therapy, a high-risk high-reward area of research from the very beginning. The biggest success stories came recently in the treatment of X-linked severe combined immunodeficiency (SCID,) the so-called "bubble boy" disease. But the course of true therapy never did run smooth, and there have been potentially dire complications.

SCID is fortunately rare, because it's a bad-news condition. Patients are essentially left without a functioning immune system, which makes everyone in that position die early from opportunistic infections. The sort of thing that would give a healthy individual a nasty cough for a few days is a fatal illness if you don't have T-cells and their partners. The most common genetic defect that lead to this condition is a loss of the enzyme adenosine deaminase, but there are several others that will put you in the same boat. The recent good news/bad news incidents concen SCID which was mediated by a loss of a protein called gc (for gamma-chain,) which is involved in cytokine signaling. There are some significant differences in trying to treat these two varieties, but gc-loss is probably easier to treat (a relative judgement if ever there was one; they're both tough.)

The standard therapy is bone marrow transplantation. This uses tissue from a matched healthy donor, usually after some level of intentional destruction of the existing marrow. When things really are matched identically, the prognosis is excellent, but the problem is that finding such a tissue match isn't always easy. A lesser degree of similarity, HLA-haploidentical tissue matching, is the next option. Survival rates in those cases are lower, although still around 75%, which most surely beats an early and certain death. But these patients don't usually get the full range of their immune response back. Specifically, B cells and NK cells aren't restored to normal levels, and even T-cell counts can start falling with time.

So there's room for improvement, and if you're a patient for whom no good tissue match exists, there's room for a lot of improvement. Thus gene therapy. The basic idea is similar to using bone marrow from a donor, only you donate your own marrow, newly refurbished, to yourself. The original marrow cells are replaced with genetically altered cells which have had the proper gene spliced into them.

Which sounds reasonably simple, but getting the gene into the cells is the voodoo part of the whole sequence. There are any number of ways of doing that, each with their known advantages and disadvantages, and each with plenty of unknown things waiting to emerge. Much of the progress in gene therapy has come from refining the vectors used to introduce the genes, but it's still a pretty crude process. In the standard method a crippled form of a retrovirus is used, one without RNA sequences for some key proteins that it would need to reproduce itself.

The problem is, these retroviruses go around jamming in genetic material all over the place. Sometimes it'll end up in a place where it can get transcribed into active protein, and sometimes it won't. If it inserts right into the middle of some key cellular gene that has to be read off later, the cell will probably die when it tries to do that. You just incubate as many stem cells as you can get, and hope for the best.

In several of the patients, that's what they got. They seem to have completely restored immune systems, a first for non-tissue-matching SCID patients. But in one case, the gene appears to have inserted itself into precisely the wrong place, making nonsense out of a gene that codes for a known growth-checking protein called LMO-2. This could have happened in only one cell out of the entire transplant, but one cell is enough. Loss of this protein has sent it into full-tilt reproduction and growth, which is another word for cancer. A new man-made form of leukemia was the result.

Analysis of the proliferating T-cells showed that, indeed, the necessary protein had the viral sequences wedged into it. The boy involved has a family history of a higher incidence of tumors, and he had a chicken-pox infection after his transplant (which must have been a scary test of its efficacy.) Either of these could have made the situation worse. He's receiving chemotherapy now, and as of last report the prognosis is cautiously optimism that the rogue cells can be brought under control.

So, does this stop the gene therapy world in its tracks? Not at all, as it turns out. In what I think is a very realistic risk/reward appraisal, an FDA advisory committee met last week and decided to press on with such experiments in the US. After all, it's the only chance these patients have. And a pediatric oncologist for the National Cancer Institute put it well: "If we threw out every therapy in cancer that causes cancer," she said, "we would get rid of some of our most effective ones." For better or worse, that's the state of the art. Good luck to all involved.

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