The original work started with Schimmel, who had been studying RNA synthetases for a number of years.
After a gene is transcribed from double-stranded DNA into a single-stranded form of RNA called messenger RNA (mRNA), a large molecule called the ribosome translates the mRNA into a protein. The ribosome recognizes another type of molecule, transfer RNA (tRNA), which brings the ribosome the amino acids from which it constructs proteins.
One of the first steps of protein synthesis involves "charging" the tRNA molecules with the amino acids, and this step is carried out by a set of molecules known as tRNA synthetases. TrpRS, for instance, charges tRNA molecules with the amino acid tryptophan. Since protein synthesis provides the raw material during angiogenesis, tRNA synthetases play a big role. And, indeed, several years ago, Schimmel showed that a full length tyrosine tRNA synthetase served as a pro-angiogenic molecule.
Noticing that another similar enzyme, the tryptophanyl tRNA synthetase "TrpRS", had similar motifs as the tyrosine enzyme, Schimmel and his laboratory reasoned that like the tyrosine tRNA synthetase, the TrpRS would promote angiogenesis. Much to his amazement, however, TrpRS not only was not a promoter of angiogenesis—it actually inhibited the process.
This was a surprising result, since one would not expect a molecule involved in protein synthesis and cell proliferation to be involved in shutting down that same proliferation.
"Then," says Schimmel, "a talented postdoctoral student in our laboratory—Kei Wakasugi—had the original idea that a fragment of human TrpRS could be active in angiogenic pathways."
Interestingly, two naturally occurring, shortened forms of the molecule proved to be even more powerful inhibitors of angiogenesis. These truncated forms are either made after one end of the full-size TrpRS is chopped off by proteolysis or they are synthesized from an "alternatively spliced" mRNA, which has been rearranged by the cell before the ribosome uses it to make a protein.
Wakasugi and others in the laboratory did many tests and established that the TrpRS fragments were, indeed, inhibitors of angiogenesis in cell culture. But Schimmel and his laboratory wanted to test the TrpRS fragments using more powerful models, such as those that Friedlander had already developed over the course of studying angiogenesis for several years. In this model system normal vessel formation in the eye resembles, in many ways, the type of angiogenesis observed in human neovascular eye disease.
"We were then fortunate to have wonderful collaborators here at The Scripps—the laboratories of Marty Friedlander and David Cheresh—who gave us the opportunity to then extend the work by testing two of the fragments in animal models that they had specifically developed for angiogenesis," says Schimmel.
In the subsequent experiments, they confirmed the earlier findings and extended them by demonstrating the TrpRS fragments were potent anti-angiogenics.
The fact that TrpRS is a naturally occurring protein may make it an even more effective treatment because it will not have the same problems of toxicity and immunogenicity that plague some other potential drugs.
"Moreover," says Friedlander, "this is something that we can teach the cell how to make." One clinical approach to treating angiogenic vision loss, he says, could be to deliver the TrpRS molecules directly into the eye through gene- and cell-based vectors.
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