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We have reported on the research of a small public company, IBEX Technologies in Montreal, Canada for the past two years (Fall 1997 and Fall 1997 newsletters). Their goal is to provide an adjunct treatment to the diet which would allow a significantly greater intake of dietary phenylalanine. The approach involves crystallizing, then encapsulating an enzyme (phenylalanine ammonia lyase, or PAL) that metabolizes phe. Encapsulation is necessary to protect PAL from being broken down by intestinal enzymes. The company hopes to deliver the enzyme intact into the gut through a "pill," where it would act to capture excess phe.
A new medical journal article in the Proceedings of the National Academy of Sciences (vol. 96, 2339-44, March 1999), reported that the company has found a way to produce large quantities of PAL by inserting the gene for the enzyme into E. coli bacteria. The enzyme is produced in large quantities by the bacteria, then purified. "Until now, the cost of PAL has prohibited any consideration of therapy; even animal studies were curtailed," say the authors.
The article also reports that in mice genetically engineered to have high blood phe levels, there was an approximately 50% reduction in blood phe levels after injection of the purified enzyme. The PAL was protected from degradation in the gut by retaining and shielding it in the E. coli cells where it was produced (not an option in humans). This study proved that PAL can work to reduce blood phe, though at least a 70-80% reduction in blood phe levels would be necessary for treatment of PKU.
This article and a summary that recently appeared on the Internet generated considerable excitement from the PKU community. When I asked Paul Baehr, CEO of IBEX, to comment on the progress being made, he told me that this article was a good example of the gap that lies between "the enthusiasm of research and the realities of developing a drug." Here is his viewpoint on the PKU research at IBEX:
"While we have made progress since the last time the newsletter reported on our research, we are not yet able to say that we have a drug candidate worthy of taking into the expensive developmental process. Virtually all the progress we have made is at the scientific level. While exciting from the point of generating new data, it does not bring us closer to having a commercially viable compound.
The main obstacle is still the development of an affordable production process for PAL. While we have been able to increase the yield well beyond the previously published levels, they are still well short of what is needed, by at least one order of magnitude.
The second problem is protection of PAL in the gut. The gut enzymes chew up PAL extremely quickly. Therefore, to get an appropriate therapeutic load, we would have to give an unacceptably high dose. This would not only be uncomfortable for the patient, it is impractical for production in that there are no existing pharmaceutical facilities that have the required capacity.
These are problems we have to overcome before we can even put the compound into safety and later clinical testing (as outlined in the Fall 1998 newsletter). We continue to think about the problem, and no new idea goes without investigation, but I’m afraid that until we find a production breakthrough.