Important note: Information in this article was accurate in July 2004. The state of the art may have changed since the publication date.
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Project Inform Perspectives 38 - July 2004
Entry inhibitors are a new class of anti-HIV drugs that work by blocking the virus’ ability to infect a cell. There are two general types of entry inhibitors: fusion inhibitors and attachment inhibitors. They may be joined by a third type in future years.
Enfuvirtide (T20, Fuzeon), a fusion inhibitor approved by the Food and Drug Administration in 2003, is the first of this new class available for wide scale use. While enfuvirtide has proven to be potent, its side effects, mostly associated with the fact that it has to be injected with a syringe, have discouraged many people from using it. Still, others have been denied access because of the extremely high cost of the drug, which prevents many states from including it in their AIDS Drug Assistance Programs (ADAP). For more information on enfuvirtide, call Project Inform’s toll-free hotline at 1-800-822-7422.
Many believe the greater promise for entry inhibitors will be realized with small molecule drugs. When large molecule drugs, like enfuvirtide, are taken orally, the digestive process breaks them into smaller pieces, thus rendering them ineffective. Therefore, they must be taken by injection. Small molecules drugs, however, are unaltered by the digestive system and can be taken by mouth, avoiding the problems associated with injections. Several are in development, including six that are in human studies, which we report on here.
HIV viral entry involves four steps. First, the virus attaches to the CD4+ protein, a receptor that appears on certain cells of the immune system. Then, it binds to a second surface protein on these cells, called a co-receptor. The most common co-receptors for HIV are CCR5 and CXCR4. Once it’s anchored to the two receptors, the virus fuses its outer coat to the coat of the cell. Lastly, HIV sheds its own coat and injects its genetic material from its core into the cell.
There are compounds in development that target each of these entry steps. Most are still in test tube studies. The six entry inhibitors currently in human studies can be divided into two categories—those that block the first step (virus attachment to the CD4+ protein) and those that block the second step (binding to a co-receptor).
is an oral attachment inhibitor drug that binds to CD4+ receptors. By binding, it blocks the virus from attaching to the cell. It is currently being studied at two doses, 800mg and 1,800mg, twice a day. Preliminary data show that among the 12 people who were given the lower dose (800mg twice daily), viral load decreased an average of .73 logs compared to .02 log decrease among the three people who received a placebo. Information was not presented on the higher dose group, but will be forthcoming. Further studies are being planned.
is a monoclonal antibody of CD4+. It’s a man-made antibody, binding to CD4+ cells in hopes of blocking the first step in the viral entry process—attachment to the CD4+ receptor. In a small study, 22 people were given TNX-355 by injection either weekly or every two weeks in addition to their standard anti-HIV regimen for nine weeks. Viral load reductions of approximately 1 log were observed within 2 weeks of initiating TNX-355. However, viral load returned to pre-study levels by the end of nine weeks, with evidence of resistance. CD4+ cell counts fluctuated during the study, and maximum increases ranged between 103 and 257, with greatest increases being seen among those receiving weekly injections. One inherent limitation of many monoclonal antibodies is that the human body sometimes makes antibodies against the antibody, diminishing their effectiveness. An additional concern is that monoclonal antibodies are very expensive to make in the large quantities needed for chronic treatment.
from Progenics, mimics CD4+ cell receptors, causing HIV to bind to PRO 542 instead of CD4+ cells. In one study of heavily pre-treated people whose drug regimens were failing, viral load reductions of 60–80% were seen after a single dose of PRO 542. The results are promising and follow-up studies are planned. However, the drug must be given by subcutaneous injection, a clear liability.
is a small molecule oral drug that binds to the CCR5 receptor and thus prevents HIV from binding to this co-receptor. Recent data from a small dose finding study were encouraging. A total of 36 people, who were not on other anti-HIV drugs, received one of 4 doses (10mg, 25mg and 50mg) of Schering D every 12 hours for two weeks. An additional 12 people received a placebo. Viral load decreases were reported in all groups receiving Schering D, with the largest decrease seen at the highest doses (-1.08 logs, -1.56 logs and -1.62 logs respectively). No significant changes in viral load were seen in the placebo group.
is another oral CCR5 blocker. Data presented last year from a small dose finding study, show it to be potent and well tolerated. A total of 16 people were given UK-427,857 at two dose levels and were compared to eight people given a placebo. At the higher dose, 100mg two times a day, seven out of eight people had a 1 log reduction in HIV viral load. Half the people taking the lower dose of 25mg two times a day had viral load decreases of greater than 0.5 logs. No serious side effects were reported in the study. As is the case with the Schering D drug, it is not clear whether the optimal dose has yet been determined for this drug.
is also an oral CCR5 blocker. In a small safety and dose finding study, the drug was found to be safe, with no serious side effects reported. The most common side effects were nausea, diarrhea and abdominal cramping. No data on anti-HIV effects were reported. Follow-up studies are planned.
The promise of entry inhibitors, especially small molecules, has many companies working on their own novel drugs. Many are still in pre-clinical development, and are years away from being available. However there are a number of promising candidates already in human studies. If these continue to show promise, some might reach wider human use within two or two and a half years.
People living with HIV need drugs that address new targets, which are easier to take and have fewer side effects. Entry inhibitors hold promise in these ways, but as always, the proof will come from clinical studies.
Manipulating the body’s cells and genes to treat disease holds great potential, but it is a field of research in its infancy. It will likely not yield results for years or perhaps decades as it takes baby steps towards progress. And although dramatic advances in treating HIV are not expected to come soon, its byproducts—such as information about the immune system and HIV infection—may contribute to short-term advances. This article provides an overview of the reasons for and challenges of gene therapy research.
Your immune system includes many parts: thymus, lymph nodes, bone marrow, etc. The cells in your body are made from cells found in your bone marrow. One special cell found in bone marrow, called a stem cell, is sometimes called the mother of all cells. If your immune system is intact and working well, then a single stem cell could divide and populate the full range of cells in your body.
Imagine there’s a gene that makes a cell resistant to HIV infection. In theory, if that gene was inserted into a stem cell, all of the offspring of that cell would carry the gene and be resistant to HIV infection.
Again, in theory, as HIV destroys a person’s CD4+ and other immune cells, the new cells resistant to HIV would replace them and thrive. Eventually these newer cells would take over and HIV could no longer weaken the immune system. Although a person may still have HIV, it could do no harm. The HIV may just die out because there are no cells for it to infect; or, it might persist but couldn’t harm the immune system to any great degree.
The success of using gene therapy to treat HIV rests on some important assumptions. The first is that all parts of the immune system must be intact in order to support the stem cells in repopulating the system. However, some researchers suspect that HIV may damage the thymus. So, at some point in a person’s HIV disease the thymus may not help develop new healthy CD4+ cells. Other therapies may need to be used to improve or enhance damaged immune environments (such as the thymus or bone marrow) in order for gene therapy to be successful.
Assuming that the thymus, bone marrow and other immune environments are functioning well, the next challenge is finding a gene that makes a cell resistant to HIV infection. Once it has been identified, it’s necessary to get that gene into a cell. Some researchers are experimenting with injecting these genes directly into muscle, called direct DNA injection. However, most researchers believe that the most effective way to get a gene into a cell is by “packaging” it into a virus. Viruses that scientists use to deliver genes, called vectors, include the Adeno-associated Virus (AAV) and maybe even crippled versions of HIV.
Getting a gene into a cell is no small feat. Not only must it be passed into the cell, but it must be done without harming it. It must also get into the gene without causing disease itself (and/or without combining with another virus, like HIV, and then causing disease).
In other gene therapy experiments for HIV, researchers have removed and genetically changed stem cells. However, when the new cells were infused back into the body, other immune cells detected that they had been altered and destroyed them. Therefore, it’s not merely a matter of getting the gene into cells but doing it in a way that doesn’t let the other cells target and destroy the new cells.
Once a stem cell is changed with a protective gene, and it remains functional and not targeted for destruction, the next challenge is making sure the stem cells begin dividing and that their offspring carry and use the protective gene. Of course, it’s key that the new cells aren’t also targeted and destroyed. While the ideal target for gene therapy may be stem cells, researchers are also looking at altering their offspring CD4+ cells. This would help rid at least one of the challenges in stem cell research.
The challenge of getting genes into cells occurs in all gene research, from HIV to cancer to genetic deficiencies. The solutions will probably come from combining the findings from these fields of research. However, there are still many concerns about safety, and they must be addressed carefully.
Carl June at the University of Pennsylvania has reproduced CD4+ cells (not stem cells) that are resistant to HIV. His group has altered these cells with an HIV-based lentiviral vector that carries a gene targeting HIV, called HIV antisense. Together with ViRxSys, his group changed a large number of cells (above 90%) in the lab.
One small study is focusing on collecting safety information on five volunteers who have failed at least two anti-HIV regimens and have HIV levels above 5,000. They each will get one dose of these altered CD4+ cells. Their HIV levels and CD4+ cell counts will be checked along with the number of days that these cells persist.
Jan Van Luzen, through the Universities of Frankfurt and Hamburg in Germany, is developing a small study of gene therapy aimed at blocking HIV’s entry into cells. (This is similar to the anti-HIV drug, T20.) The gene is called M87oRRE and the vector being used is called myloproliferative sarcoma virus. Van Luzen will alter CD4+ cells using Carl June’s methods. The study will enroll ten people who are resistant to all classes of anti-HIV therapy and have CD4+ cell counts below 200. The first volunteer was treated by injection in January 2004. So far, no data are available.
Researchers in the U.S. and Australia have developed a mid-sized study of gene therapy that targets the tat gene. The gene, called Rz2, is a hammerhead ribozyme and can potentially stop HIV at five places in its replication cycle. It is passed into stem cells using a retroviral vector, one that has already been evaluated for safety in over 50 studies.
This study will enroll over 70 people. Volunteers must have CD4+ cell counts above 300, and have been on anti-HIV therapy with HIV levels below 50 for at least six months. The study will include an interruption in anti-HIV therapy in order to assess the anti-HIV activity of the gene.
Data from a ten-person phase I study of this approach suggest that it’s safe. (There were no safety concerns, and some volunteers have been followed for three years.) The Rz2 gene was found in the new cells in all volunteers. The study is enrolling at UC Los Angeles (Dr. Ron Mitsuyasu), UC Stanford (Dr. Tom Merigan), San Francisco (Dr. Steven Becker), and St. Vincent’s in Sydney (Drs. Cooper and Carr).
Several studies using gene therapy to treat HIV have started over the past few years. Over the past decade, however, gene therapy research in general has been a rollercoaster of enthusiasm and disappointment. The darkest period struck just a few years ago when a volunteer in one experiment died due to complications from the procedure.
All human gene therapy research was stopped for nearly two years until the cause of death was evaluated and safety concerns were addressed. More recently there has been a renewed enthusiasm as gene therapy has successfully treated some other conditions. Advances in technology are also overcoming other challenges in the field.
Gene therapy research still faces many challenges, in addition to those outlined in this article. They include the need for increased public funding for biomedical research and the short-sightedness of biotech and drug companies investing in the future. It also includes the hurdles faced by independent researchers struggling to turn novel ideas into useful therapy for the patient.
Several years ago there was much enthusiasm for the RevM10 gene being researched in partnership with Systemix Corporation. Systemix was then bought by a larger drug company, and both gene therapy and HIV didn’t fit into their development plan. The studies were stopped and the program was shut down.
Although gene therapy research won’t offer a quick cure for AIDS, it is becoming an increasingly important part in the future of HIV treatment. It offers a new frontier for a cure, with great hope for promising new treatments.
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