Jan. 3, 2002 A potentially potent inhibitor of angiogenesis, the process whereby new blood vessels are formed from existing ones, can be found in one of the very molecules involved in the same process. This finding, made by two scientists from The Scripps Research Institute (TSRI), may lead to new therapies, as abnormal angiogenesis is the leading cause of vision loss in the United States.
In the current issue of the journal Proceedings of the National Academy of Sciences, two reports by collaborating authors from TSRI describe the antiangiogenesis activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS). The reports are authored by Paul Schimmel, Ph.D., Ernest and Jean Hahn Professor, Chair of Molecular Biology and Chemistry, and member of The Skaggs Institute for Chemical Biology and Martin Friedlander, M.D., Ph.D., Associate Professor in the Department of Cell Biology and Chief of the Retina Service in the Division of Ophthalmology, Department of Surgery at Scripps Clinic.
"There are many potential applications [for TrpRS], ranging from blindness to cancer, that we want to pursue," says Schimmel.
Angiogenesis is a natural biological process that can sometimes go awry. Abnormal angiogenesis is the cause of age-related macular degeneration (ARMD) and diabetic retinopathy, diseases that afflict tens of millions of Americans and cause catastrophic vision loss in many.
Both of these eye diseases are characterized by the development of abnormal blood vessel growth in the eye. In the case of ARMD, new blood vessels grow under the retina. In diabetic retinopathy, abnormal vessels grow on top of the retina. The effect is much the same; the vessels interfere with normal structures or the transmission of light to the back of the eye, impeding vision. There is currently no effective treatment for the vast majority of these patients.
There are several antiangiogenic compounds in clinical trials. But TrpRS, says Friedlander, appears to be more potent.
"People typically talk about 20, 30, 40 percent inhibition [of new vessel formation] for the compounds that are in clinical trials," says Friedlander. "What we have seen in our pre-clinical studies is that in 70 percent of cases, you get 100 percent inhibition."
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.
These are applied questions that Friedlander and Schimmel are just beginning to explore. At the same time, they are pursuing the basic science questions of the mechanisms and evolutionary meaning behind TrpRS inhibition of angiogenesis.
Cells undergo proliferation of blood vessels as a response to inflammation, infection, or ischemic blockage of blood flow. The raw material for this proliferation is the proteins cells express through their genes.
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, molecules like TrpRS play a big role.
Interestingly, two naturally occurring, shortened forms of the molecule have proven to be 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.
This dual role for TrpRS surprised Schimmel and Friedlander, because they did not expect a molecule involved in protein synthesis and cell proliferation to be involved in shutting down that same proliferation.
In nature, TrpRS could be controlling the direction and perhaps the termination of blood vessels, and organisms may have evolved to use the shortened form of TrpRS to regulate angiogenesis because the full-size protein was already at the site of proliferation.
"We're trying hard to figure out what role [the alternatively-spliced fragment] plays in nature," says Schimmel. "The key thing that we have to do now is identify its receptor."
The research article "A human aminoacyl-tRNA synthetase as a regulator of angiogenesis" is authored by Keisuke Wakasugi, Bonnie M. Slike, John Hood, Atushi Otani, Karla L. Ewalt, Martin Friedlander, David Cheresh, and Paul Schimmel and appears in the January 2, 2002 online issue of Proceedings of the National Academy of Sciences.
The research article "A fragment of human TrpRS as a potent antagonist of ocular angiogenesis" is authored by Atushi Otani, Bonnie M. Slike, Michael I. Dorrell, John Hood, Karen Kinder, Karla L. Ewalt, David Cheresh, Paul Schimmel, and Martin Friedlander and appears in the January 2, 2002 online issue of Proceedings of the National Academy of Sciences.
The research was funded by the National Eye Institute, The National Cancer Institute, The Skaggs Institute for Chemical Biology, The Robert Mealey Program for the Study of Macular Degenerations, the ARCS Foundation, and the National Foundation for Cancer Research.
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