‘Molecular Scissors’: New Hope for AIDS : Medicine: The artificially prepared form of RNA interferes with the infection of cells by the virus.

An innovative “molecular scissors” that interferes with the infection of cells by the AIDS virus has been developed by researchers at the City of Hope National Medical Center in Duarte.

Molecular geneticist John J. Rossi and his colleagues report today in the journal Science that they have used a specially prepared form of RNA (ribonucleic acid) to create the scissors, which snips apart the virus’ own RNA before it can be used as a blueprint for replication of the virus.

The scientists have already inserted a gene for the artificially prepared RNA, called a ribozyme, into cultured human cells and shown that it sharply reduces infection of the cells, which should halt the progression of the disease. They are now working with Vestar Corp. of San Dimas to develop a way to deliver the ribozymes into the white blood cells of AIDS victims, where it would halt the replication of the virus.

Nava Sarver, who is in charge of the National Institutes of Health’s program for rapid development of new AIDS therapies, predicted that human trials could begin in as little as three years.

The principal advantage of the technique is that it is extremely selective in its activity, attacking only the viral RNA and leaving the cell’s own genetic materials intact. This approach to therapy should therefore produce virtually no side effects, unlike currently used drugs such as AZT.

Many researchers believe that this approach may ultimately provide a completely new way to attack all kinds of viral infections, which are now almost impossible to treat.

“It’s a promising approach,” said molecular biologist Sidney Altman of Yale University, “but we have to keep in mind that every year many promising approaches are discarded because they don’t work.”

Perhaps ironically, the lineage of the ribozymes that would be used to attack humanity’s newest infectious nemesis can be traced back to the oldest molecules on Earth, the ones that were present when life first arose.

Many researchers now believe that the first life on Earth was composed entirely of RNA, which combined the functions of DNA (deoxyribonucleic acid), which carries the genetic information necessary for life, and proteins, such as enzymes, which carry out the biochemical functions necessary for life.

Previously, researchers had believed that the primary function of RNA--except for a few viruses, such as the AIDS virus--was to serve as an intermediate between DNA and proteins. RNA provides a sort of working blueprint for cellular machinery, a copy of genetic information from DNA that is used in the production of proteins.

In the early 1980s, however, Altman and molecular biologist Thomas Cech of the University of Colorado in Boulder independently discovered that RNA could act in the same fashion as enzymes, cutting apart RNA and moving it around in cells. Their discovery earned them the 1989 Nobel Prize for Chemistry.

Immediately, many researchers saw the ribozymes as a new way to attack viruses and began developing ways to use them. Rossi and his colleagues are apparently the first to report success.

Rossi and his associates took a fragment of RNA--the “scissors” portion of the molecule--from a plant and combined it with an artificially synthesized RNA fragment that would bind only to RNA that serves as a blueprint for a protein crucial to replication of the AIDS virus (which is known formally as the human immunodeficiency virus or HIV).

In the test tube, they found that the ribozyme thus produced would in fact bind to the target RNA from the AIDS virus and cut it.

They next used genetic engineering techniques to insert the gene for the ribozyme into human cells grown in a test tube. The cells produced the ribozyme and, when the researchers infected the cells with HIV, the ribozyme prevented the virus from reproducing and spreading.

Most important, he said, the ribozyme “only targets what you ask it to target. And it’s a natural molecule, so the cell sees it only as RNA, not as a toxic drug.”

Vestar and a half-dozen other companies around the country are developing a promising new way to deliver ribozymes. They encapsulate the ribozyme in an artificial sphere, about one-hundredth the size of a red blood cell, called a liposome.

The liposome is composed of naturally occurring fat molecules that surround the drug to be carried and protect it from degradation in the blood stream. Theliposomes are also readily taken up by cells, so they provide a method of injecting the drug into target cells. Inside the cell, the fat molecules are absorbed, freeing the drug.

The liposomes, like the ribozymes, are still largely experimental, although Vestar just received approval in Italy to market an anti-fungal agent carried by lipsomes.

Consequently, said biochemist Sean Sullivan of Vestar, a great deal of testing will be required before the technique can be studied in humans. “But in all fairness to NIH and FDA (the U.S. Food and Drug Administration), any therapeutic that looks promising gets put on a fairly fast track. So the process could be accelerated.”