Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 9 - October, 1993
Michael Ravitch

Background and Overview

All viral infections, including AIDS, can be described as acquired genetic diseases. Viruses are packages of genetic material that insert themselves into DNA, the double-stranded chain of genes inside the nucleus of every cell, and transform the cell into a factory for producing new copies of the virus.

Each sequence on the DNA provides the blueprint for the production of a specific protein. Proteins are complex structures which form the building blocks of all life. Human DNA contains all the necessary information to produce the proteins that compose our bodies. However, once infected by the virus, the DNA also programs the cell to manufacture the component proteins of HIV.

In order to produce proteins, the DNA must transmit its information to a messenger RNA (mRNA) molecule, also known as the sense strand. The mRNA uses this information to organize the building and assembly of proteins into the finished product -- usually essential cellular components but, in the case of infected cells, new copies of HIV. An anti-sense drug is the exact opposite (i.e. the mirror image) of a specific "sense" strand. Antisense drugs attach to mRNA, and thereby block the production of particular proteins at the genetic level.

Traditional drugs attack proteins, which, in the case of anti-HIV treatments, include reverse transcriptase, protease, and other familiar targets. However, proteins are large, complex structures that are produced in massive quantities by infected cells. In order to be successful, traditional drugs must disable every copy of the protein. Traditional drugs often attack healthy, normal proteins as well, and cause toxicities. Antisense is an attractive option because each mRNA molecule produces large numbers of each protein. Anti- sense technology, by attacking a single mRNA strand which is responsible for producing large quantities of single protein, may be a more efficient way of eliminating large quantities of unwanted proteins at once. Since an antisense drug only binds with its exact opposite, it should be extremely specific, producing minimal toxicities.

Whereas proteins are large and complex, RNA is composed of various combinations of just four well-known amino acids -- adenosine, cytosine, thymidine, and guanosine.

Antisense proponents have discovered that the real world does not follow theory as quickly nor as easily as they would like. As simple and elegant as it seems, antisense has not yet translated into clinical reality. The technological challenges are numerous. Since antisense drugs will be administered in traditional ways -- intravenously or subcutaneously -- scientists face significant hurdles. The compounds must be large enough to be extremely specific to the right piece of RNA, but stable enough to avoid destruction by the body, and small enough to reach and penetrate target cells. Chemists have been modifying antisense compounds for years in order to solve these problems, with as yet unknown success.

Even with an optimal compound, the therapy, in the case of HIV at least, would have to be taken chronically, and probably in high doses. Viral resistance, as with regular antivirals, could theoretically develop. Furthermore, the expense could be staggering because large-scale production of these compounds is still costly and difficult.

For all these reasons, the first efforts with antisense drugs have been for topical, rather than systemic, uses. The first antisense drug to enter clinical trials was a therapy aimed at genital warts caused by Human Papilloma Virus (HPV). Isis Pharmaceuticals, a Seattle-based biotechnology company, began this first antisense trial in 1992. Thus far, the company has no evidence of efficacy, but reports about absorption and safety are promising. Again, this is only topical use, and its lessons for systemic HIV therapy are limited.

The First AIDS Trial

Hybridon, a Worcester, MA-biotechnology company, seems poised to put the first systemic antisense drug into HIV-positive individuals. GEM-91, its lead compound, blocks HIV's gag gene. The gag gene of HIV is common to all retroviruses and encodes for the critical core proteins of HIV, such as p9, p17, and p25 (the nucleiod shell). If gag, production is blocked, the Hybridon investigators theorize HIV replication could be dramatically slowed. Phase I trials are currently planned to begin in United States at the University of Alabama at Birmingham and through the ANRS, the French national AIDS research network. The French study could enroll its first patient in October.

Hybridon believes GEM-91 may have two unique features. Laboratory studies indicate mRNA may not be the only target. HIV, like all other retroviruses, enters the cell as a piece of viral RNA (vRNA). GEM-91 may also inhibit vRNA before its integration into DNA. This suggests that GEM-91 might interfere with both early and late stages in HIV's replication cycle. Hybridon also claims another advantage to its compound over the traditional antisense model. Instead of merely disabling a single RNA strand, its drug might be able to destroy many RNA strands. According to Hybridon, GEM-91 first binds to the target RNA strand, then activates a cellular enzyme (RNAseH) which destroys the strand, leaving the drug free to attack more RNA.

Even if GEM-91 fails in humans, Hybridon is positioned to be a leading player in antisense research. Hybridon has already synthesized GEM-92, its second generation product. Also, the company claims broad patent rights over all antisense approaches to AIDS, although this has not been tested in the courts.

In addition, Hybridon believes it has resolved manufacturing issues. The company was recently awarded a patent that covers new, more efficient methods of antisense production and has started construction of a large manufacturing facility. The company believes that it will have sufficient supply of the compound to meet the needs of clinical research.

Conclusion

Since the genes of HIV have been extensively studied by molecular biologists, researchers can design antisense compounds aimed at specific mRNA molecules that produce proteins essential to HIV's survival. Although very few clinical trials have actually begun, and clinical efficacy is a long way from certain, the pharmaceutical industry has devoted significant resources to this burgeoning field. Its proponents believe antisense will radically transform medicine and open up the possibility for new treatments for AIDS and other viral diseases.

Other Gene Modulators in Development

Other gene therapy approaches similar to antisense are in more preliminary stages of development.

Triple Helix DNA

An innovative twist on the antisense idea is the "Triple Helix" technology being developed by several companies. Whereas naturally-occurring DNA consists of two interlocking strands in the famous double helix structure, scientist have developed the means to attach a third strand of DNA to the double helix, effectively blocking transcription. Now they are working to synthesize small strands of DNA which are targeted against specific sequences of the HIV genome. In the same way that RNA-targeted therapeutics are more efficient than drugs which bind with proteins, Triple Helix promises to be more efficient than conventional antisense. The compound would bind to the DNA itself, rather that to the thousands of mRNA transcripts. Thus less drug would be needed, greater efficacy would be achieved, and transcription of the unwanted gene would cease completely. However, this technology is at an earlier stage of development, and many biochemical obstacles remain.

Ribozymes

Another promising variation on antisense are a class of compounds called Ribozymes. These are naturally-occurring RNA molecules which function as catalytic molecular scissors, chopping up RNA strands at selected sites. Ribozymes can be synthesized, and targeted against specific RNA sequences, just like antisense compounds. However since ribozymes can effectively destroy many targets, according to its proponents, lower levels of drug might be needed, and therapy could be more thorough.

However, chemists have not yet figured out how ribozymes can reach and penetrate cells in the body. Recently the RAC approved the first clinical study of ribozymes (see page 6). The investigator is Flossie Wong-Staal at the University of California at San Diego. In the test tube, her so-called "hairpin" ribozyme completely blocked HIV infection. In order to overcome the pharmacological difficulties, Wong-Staal is attempting a gene therapy double whammy: she will plant a gene in the CD4 cells of the subjects that will produce the ribozyme.

One hope is the creation of a ribozyme which can cleave DNA, rather than RNA, and thus could simply cut the viral genes out of the host cell DNA. If such a compound were in existence, it would be an extremely promising modality for HIV treatment.

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