The AIDS Beacon » Gene Therapy

Sangamo BioSciences Initiates Gene Therapy Trials Toward A Cure For HIV

Courtney McQueen — Tue, 10 Jan 2012 14:58:03 +0000

Sangamo BioSciences announced yesterday that it is initiating two Phase 2 clinical trials of its gene therapy treatments for people with HIV. The trials will test two different strategies for increasing the effectiveness of the therapy, with the goal of creating a cure for HIV.

“We are delighted to be able to open these two important clinical studies ahead of schedule,” said Geoff Nichol, executive vice president of research and development at Sangamo, in a press release.

Both trials are testing gene therapy approaches to curing HIV. In the field of HIV/AIDs, gene therapy involves modifying a person’s DNA (the genetic information in cells) so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In both trials, cells will be taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

Altogether, Sangamo anticipates recruiting around 29 people with HIV for both clinical trials.

Gene therapy as a cure for HIV is a somewhat controversial approach. Some researchers believe the technique is too risky and expensive for widespread use. Others, however, think that gene therapy may be the only way to cure HIV, and that the science behind it is developing rapidly enough to make it a viable treatment option (see related AIDS Beacon news).

The gene therapy approach being tested by Sangamo is an attempt to mimic the success of “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated form of the CCR5 gene.

HIV requires the CCR5 protein, which is located on the surface of white blood cells, in order to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV. Since his transplant, no sign of HIV has been detected in The Berlin Patient.

In the Sangamo trials, investigators will genetically modify immune cells, called T-cells, to remove CCR5. The researchers hope that the genetically modified T-cells will be immune to the virus and thus able to block viral entry and replication. They also hope the cells will multiply to make other HIV-resistant T-cells. The goal is to eventually attain a “functional cure” for HIV: a remission state with long-term control of HIV, including low viral loads (amount of HIV in the blood) in the absence of antiretroviral therapy.

Results from a Phase 1 trial showed that the technique successfully reduced viral loads in patients with HIV. One study participant, who already naturally had one copy of the HIV-resistant CCR5 gene form, achieved undetectable viral loads with the treatment.

“Both of these new Phase 2 clinical trials are specifically designed to confirm and further investigate these findings,” said Nichol.

In the Phase 2 trials, Sangamo will test two approaches to improve the efficacy of their technique.

In the first trial, the researchers will further explore the gene therapy’s effects on people who naturally have one copy of the HIV-resistant CCR5 gene. Up to 20 HIV-positive adults on antiretroviral therapy who have the alternate gene will be enrolled.

Study participants will receive one course of the gene therapy treatment. After two months, they will then stop antiretroviral therapy for 16 weeks while the researchers monitor their CD4 (white blood cell) counts and viral loads.

Participants whose CD4 counts drop below 350 or whose viral loads rise above 100,000 copies per milliliter will restart therapy, as will participants with detectable viral loads after 16 weeks. However, participants who retain undetectable viral loads will remain off therapy until their viral loads become detectable or their CD4 counts drop below 350.

In the second trial, researchers will test whether an initial preparative regimen of cyclophosphamide (Cytoxan) prior to the gene therapy treatment improves its efficacy.

Cyclophosphamide is used in cancer patients to improve the outcome of stem cell transplants by killing a patient’s existing T-cells. The goal of the trial is to determine if depleting these cells will allow the gene therapy-modified T-cells to better take hold and multiply.

The trial will enroll at least nine participants and will test three different dosages of cyclophosphamide a day prior to the gene therapy treatment. After the gene therapy treatment, study participants will then undergo a 16 week antiretroviral treatment interruption with the same guidelines as in the first trial, but with a more stringent CD4 count cutoff of 500 cells per microliter.

For more information, please see the Sangamo BioSciences press release.

An Interview With AmfAR’s Dr. Jeffrey Laurence: Part 2 – Working Toward A Cure

Courtney McQueen — Fri, 02 Dec 2011 14:36:47 +0000

This article is the second part of a two-part interview with Dr. Jeffrey Laurence, senior scientific consultant for the Foundation for AIDS Research, on the Foundation’s efforts toward a cure for HIV. Part 1 discusses the possibility of a cure and why it is necessary. Part 2 discusses the Foundation’s cure research and some promising avenues toward a cure.

Thirty years after the start of the AIDS epidemic, scientists and researchers know more than ever about the elusive and difficult-to-treat HIV virus. And, with the first-ever example of a person cured of HIV – the so-called Berlin Patient – scientists are once again starting to look toward a cure.

One of those working toward a cure for HIV is the Foundation for AIDS Research (amfAR). Founded in 1985, the Foundation to date has awarded around $325 million to HIV and AIDS researchers.

“Historically, amfAR has looked to see where the gaps were in AIDS research – things that were promising but weren’t being funded by federal programs – and have stepped in. [AmfAR] also funds things that are just too offbeat,” said Dr. Jeffrey Laurence, senior scientific consultant at amfAR and a professor of medicine at New York Hospital-Cornell Medical Center in New York City.

In an interview with The AIDS Beacon, Dr. Laurence discussed some of the avenues toward a cure that he and amfAR think are most promising.

Gene Therapy

Like other research organizations, one focus of amfAR is on gene therapy, with the goal of replicating the success of the Berlin Patient, who was cured of HIV using a bone marrow stem cell transplant from a donor whose cells were resistant to HIV infection.

Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying a person’s DNA (the genetic information in cells) so that it becomes, for example, resistant to HIV.

According to Dr. Laurence, amfAR is working on methods to produce the same result as in the Berlin Patient using a person’s own cells rather than a donor’s.

“We’re interested in whether there is a way to use…a much more practical method based on gene therapy to cure HIV in someone’s own body, in a person’s own cells, so they don’t have to go through that complex donor transplant,” said Dr. Laurence.

For the most part, gene therapy efforts toward curing HIV are still fairly preliminary, and there are several barriers that must be overcome before it can become an effective cure. According to Dr. Laurence, one of amfAR’s goals is to help eliminate these barriers.

For example, one barrier is creating enough cells that have been modified by gene therapy to effectively grant HIV immunity. “We know how to take one cell out of your body and make it completely resistant to HIV and inject it back into you, but one cell injected back into you is not going to replenish your body,” said Dr. Laurence.

“So, one approach is, can we overcome the barrier of taking that one cell and growing it up in a test tube to the several million cells that we need, to repopulate your body?” This has been done with mouse cells, but not yet with human cells, said Dr. Laurence.

Another barrier involves making the gene therapy more efficient. “At the moment, we know how to knock out genes to make a cell resistant to the AIDS virus, but if we’re going to do it in a person’s own cells, we can [currently] knock [the gene] out in 70 percent of the cells, 80 percent of the cells. We need to knock it out in 100 percent of a person’s cells,” he said.

According to Dr. Laurence, ideas on how to address these issues were one focus of a gathering of scientists he hosted earlier this year. “We came up with some very interesting ideas as further targets for amfAR grants,” he said.

Elimination Of Latent HIV Reservoirs

Another approach amfAR is pursuing is eliminating latent HIV. Latent HIV is HIV that lies dormant and will start multiplying again if antiretroviral therapy is stopped. Current antiretrovirals cannot get rid of latent HIV.

“If the first two things [to improve gene therapy] I mentioned don’t work, and we can’t replace every cell in your body with your own cells that have been genetically modified, as we can in mice, then we’re going to have these barriers of latent cells,” said Dr. Laurence.

Eradicating latent HIV is a major focus of current amfAR efforts. Aside from trying to find drugs to activate latent HIV and make it susceptible to antiretrovirals, which is being pursued by several research groups, amfAR also has some more unusual strategies it is pursuing.

One of these is to try to find indicators that a cell might be infected with latent HIV so that the entire cell can be destroyed. “[The infected cells] may be Trojan horses, that is, for all the world they look like a normal horse or a normal cell, but there’s got to be some sort of signal on their surface that says they’re not completely normal, that’s there a virus lurking inside of them,” said Dr. Laurence. “If we can discover the signal, then we can wake it up and attack those cells specifically.”

There are also a variety of other questions amfAR would like to answer to help figure out how to eradicate latent HIV. For example, said Dr. Laurence, “How are we going to get every single latent cell? Do we need to get every latent cell, or will some just die by attrition if we can identify markers on their surface to kill most of them off?”

To help answer these questions, amfAR recently gave research grants to a group of scientists from top universities as part of its new amfAR Research Consortium on HIV Eradication. These scientists will work toward understanding latent HIV, how it persists, and how to eliminate it.

Moving Forward

Gene therapy and eradication of latent HIV are two areas of HIV cure research that amfAR is focusing on. However, Dr. Laurence admitted that scientists do not really know yet what will work and what will not. One benefit of amfAR grants, he said, is that they often fund unusual projects that fail to get funding elsewhere.

“There are certainly all sorts of ideas out there that we’re not smart enough to think of, that will be coming out of unusual laboratories. The methods of growing cells that have been genetically modified and cure a mouse came out of a chemistry lab in California, not a biology or an AIDS lab,” he said.

In the meantime, Dr. Laurence emphasized the enormous amount of progress that has already been made in understanding and treating HIV. “There’s been tremendous progress that’s happened in what is, in medical research, a relatively short period of time,” he said.

Dr. Laurence is also confident that a cure for HIV can and will be achieved.

“I think it’s going to be a lot easier to find a cure for AIDS than a cure for cancer,” he said. Unlike cancer, HIV has a known cause, and scientists are learning more about it every day.

“I think AIDS, being a single virus that we have a tremendous amount of information on, is going to be a lot, a lot easier technical challenge than many of the common kinds of cancer that we get,” he said.

For Dr. Laurence, the progress in HIV research in the past 30 years is a symbol of hope for where the field could be and for people who have HIV in this era.

“I think that this should be a message to go out and get yourself tested, tested regularly if you’re at risk, to use all of the prevention strategies, behavioral and mechanical that we have to prevent an infection,” he said.

“If you do get infection, get yourself tested so that you can get treated early,” he added.

For more information on HIV cure research, please see The AIDS Beacon’s series on Advances And Barriers To A Cure For HIV.

Beacon NewsFlashes – September 27, 2011

Courtney McQueen — Tue, 27 Sep 2011 13:34:04 +0000

Congress Launches Congressional HIV/AIDS Caucus – Five representatives of Congress announced the launch of the Congressional HIV/AIDS Caucus last week. The goals of the Caucus are to maintain U.S. leadership in the fight against HIV and AIDS in the U.S. and internationally and to prepare for the International AIDS Conference in Washington, D.C., next year. The Caucus is co-chaired by Representative Jim McDermott from California, Representative Trent Franks from Arizona, and Representative Barbara Lee from California. It will have 59 members at its launch; additional members are expected to join in the coming weeks. For more information, please see the announcement on the Aids.gov website.

EMA Advisory Committee Recommends Approval For Edurant And Eviplera In Europe – An advisory committee to the European Medicines Agency (EMA) has recommended that Edurant (rilpivirine) be approved for the treatment of HIV in previously untreated adults with viral loads (amount of HIV in the blood) of 100,000 copies per milliliter or less. Edurant is marketed outside the U.S. by the pharmaceutical company Janssen, a unit of Johnson & Johnson. The committee also recommended that Gilead Sciences’ new once-daily combination antiretroviral pill Eviplera (rilpivirine/emtricitabine/tenofovir), known as Complera in the U.S., be approved for the same patient population. The recommendations improve the chances for approval of the drugs in Europe; a decision is expected within two to three months. Edurant was approved in the U.S. in May, and Complera was approved in August. For more information, please see the Johnson & Johnson and Gilead Sciences press releases.

Gene Therapy Successfully Reduces Viral Loads In People With HIV (ICAAC 2011) – Sangamo Biosciences released updated results on its Phase 1 gene therapy clinical trial last Sunday showing that the treatment successfully reduced viral loads (amount of HIV in the blood) in all six of the trial’s participants without the use of antiretroviral drugs. One participant, who had a genetic variation that makes people naturally more resistant to HIV, successfully achieved an undetectable viral load. Sangamo reported no major side effects from the treatment. The results were presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago. Sangamo previously reported that the gene therapy treatment increased CD4 (white blood cell) counts in people with HIV (see related AIDS Beacon news). For more information, please see the Reuters article or the Sangamo Biosciences press release.

Bristol-Myers Squibb Reports 83 Percent Hepatitis C Cure Rate In Phase 2 Study (ICAAC 2011) – Results from a Phase 2 clinical trial indicate that Bristol-Myers Squibb’s investigational hepatitis C drug BMS-790052 yielded an 83 percent cure rate after 48 weeks in previously untreated adults with genotype 1 hepatitis C when combined with peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus, Rebetol). Eight percent of participants reported serious side effects (anemia, or low red blood cell counts). Based on the results, Bristol-Myers Squibb has initiated a Phase 3 clinical trial with the drug. The results were presented last Saturday at ICAAC. For more information, please see the study (abstract) at the ICAAC website or the Bristol-Myers Squibb press release. For more information on the Phase 3 clinical trial, please see the U.S. Clinical Trials Registry.

Researchers Debate The Utility Of Gene Therapy In Curing HIV (IAS 2011)

Courtney McQueen — Thu, 04 Aug 2011 14:19:20 +0000

Is gene therapy too expensive and impractical to form the basis for a cure for HIV, or is it a promising technique with a proven track record that has the specificity required for a cure?

This question was debated by researchers at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011) in Rome last month.

In most cases of gene therapy, cells are taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

Dr. Sharon Lewin, director of the Infectious Disease Unit at Alfred Hospital in Melbourne, Australia, argued in a session titled “Controversies in HIV Cure Research” that gene therapy is not the strategy most likely to lead to a cure for HIV due to its impracticality.

“Gene therapy is scientifically flawed, high risk, and will never get to the clinic,” said Dr. Lewin in her presentation.

Dr. Lewin argued that cure strategies based on drugs that activate latent HIV are far more promising. Latent HIV is virus that lies dormant in cells during antiretroviral therapy but activates again once treatment is stopped to renew the infection.

A number of clinical trials are currently underway to test whether certain drugs can reactivate latent HIV so that it can be eliminated from the body’s cells. According to Dr. Lewin, these treatments have an advantage in that they are available now for testing, are less expensive and more general than gene therapy (which involves intensive individualized treatment for each person), and usually have side effects that are mild and reversible. This is not necessarily the case with gene therapy, which attempts to create permanent changes in a person’s genes.

In addition, she pointed out that there are at least 22 different potential drugs for targeting latent HIV that are in Phase 1, 2, or 3 clinical trials, several of which are already approved by the U.S. Food and Drug Administration for other uses.

Although she acknowledged that drugs, in general, are not as targeted as gene therapy, she also noted that researchers are working on ways to make the drugs target latent HIV more specifically, rather than affecting all the cells in the body.

Overall, Dr. Lewin criticized the practicality of gene therapy as a cure for HIV, particularly in developing countries. “We need a cure that is scalable, deliverable, and cheap,” she concluded.

Dr. Keith Jerome, from the Fred Hutchinson Cancer Research Center in Seattle, disagreed with Dr. Lewin and argued that gene therapy is indeed the correct approach for curing HIV.

“The principle has been proven in the only HIV cure to date,” said Dr. Jerome, in reference to “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated form of the CCR5 gene.

HIV requires the CCR5 protein, which is on the surface of white blood cells, in order to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV. Since his transplant, no sign of HIV has been detected in The Berlin Patient. Currently, the most advanced gene therapy strategies are attempts to replicate this success in other people with HIV.

Dr. Jerome argued that HIV is a genetic disease and therefore needs genetic treatment strategies to cure it. HIV works by incorporating itself into a cell’s DNA and then using the cell’s normal processes to replicate. Current treatments cannot remove the HIV once it has been incorporated, and Dr. Jerome argued that drugs that target DNA are not specific enough and are likely to have significant effects on other cell processes.

Instead, he said, treatments need to target and change specific genes, which means gene therapy is necessary.

Dr. Jerome did admit that more work needs to be done before gene therapy is a viable option for treatment. Researchers need to work more on developing therapies that are specific, have higher success rates in modifying genes, and do not require toxic preparative treatments before therapy, he said.

However, he noted that scientists have been making significant breakthroughs in the field and that researchers now have the necessary tools to make gene therapy work.

“Gene therapy is the path to a cure,” Dr. Jerome concluded.

For more information, please see Dr. Lewin’s and Dr. Jerome’s presentations (pptx) at the IAS 2011 conference website.

Advances and Barriers To A Cure For HIV: Part 4 – Obstacles In Finding A Cure

Courtney McQueen — Wed, 18 May 2011 18:02:24 +0000

This article is the fourth in a four-part series that investigates current research toward finding a cure for HIV, including advances, promising treatment strategies, and barriers to reaching a cure. Part 1 discusses general types of HIV cures. Part 2 discusses specific strategies for targeting latent HIV. Part 3 discusses gene therapy and therapeutic vaccines. Part 4 discusses barriers to obtaining a cure.

Although researchers are getting closer to finding a cure for HIV and have a number of promising avenues to pursue, there are still a number of barriers to a cure, some of them significant. In addition, for the most part, HIV cure research is still in fairly preliminary stages; most work is in the laboratory, not clinical trials.

In a recent review of the current most promising avenues toward a cure, Dr. Sharon Lewin, director of the Infectious Diseases Unit at Alfred Hospital in Australia, and Professor Christine Rouzioux from the Université Paris Descartes in France discussed some of the obstacles that researchers must overcome before implementing a cure for HIV.

Barriers to a cure were also discussed by physicians and researchers during a LiveChat last week on the Science Magazine website.

Unknown Risks: Potential Safety Issues With Current Approaches

One of the major problems with trying to cure HIV is that, since researchers still do not understand much of the science behind HIV infections and what a cure might do, there are concerns that current approaches toward a cure could have unforeseen consequences, including problems like cancer.

In general, the more experimental an approach is, the less scientists will know about its potential safety risks, particularly in the long-term.

For example, one of the ways scientists hope to cure HIV is by activating latent HIV, HIV that lies dormant during treatment until treatment is stopped. Many of the drugs that are being evaluated as latent HIV activators, including histone deacetylase (HDAC) inhibitors, work by affecting the way cells read and use DNA.

As a result, they raise two safety issues: the possibility that they could activate other viruses that have hidden in our DNA and the possibility that they could cause cancer.

“A theoretical risk of HDACIs [HDAC inhibitors] is that they will induce activation of other retroviruses and/or DNA viruses including cytomegalovirus (CMV), hepatitis B virus (HBV), and JC [John Cunningham] viruses which has been demonstrated in vitro [in the laboratory],” wrote Dr. Lewin and Prof. Rouzioux in their review.

Activation of other viruses has been observed in clinical trials in which participants were taking HDAC inhibitors; however, this occurred rarely, and Dr. Lewin and Prof. Rouzioux pointed out that these participants had advanced cancers and suppressed immune systems, so it is uncertain whether the HDAC inhibitors were to blame.

Another question is whether the drugs could cause cancer. “The long-term impact of HDACIs on enhancing the risk of malignancy and/or reactivation of oncogenes [cancer-causing genes]…is also unknown,” wrote the review authors.

Another treatment that raises cancer concerns is gene therapy. Gene therapy also involves changing the way cells use DNA, often by inserting new genes. If this process does not work as it should – if the new gene is inserted in the wrong place, for example – it can cause tumors to develop instead. This has been observed in some gene therapy trials.

In the most advanced HIV gene therapy trial to date, a Phase 2 clinical trial targeting the CCR5 protein that HIV needs to infect cells, there has been no evidence so far of cancer or other major side effects. However, the researchers will continue to monitor the participants to make sure they do not develop any problems longer-term.

A Cure For HIV: What Does It Mean?

Scientists also face a very fundamental problem when it comes to HIV: what does it mean to cure HIV, and how do you know or decide when someone has been cured?

If the goal of a treatment is a functional cure – reducing or eliminating the need for antiretrovirals to control the virus – then the definition of a cure is fairly simple: either patients still need antiretrovirals, or they do not. However, for a sterilizing cure – complete eradication of the virus from the body – the question is harder.

“This is almost a philosophical question,” said Dr. David Margolis, a professor of medicine at the University of North Carolina School of Medicine and participant in the LiveChat. “The only way to know if functional viruses or viral genomes [HIV DNA and RNA] are completely gone would be to study every cell in the body – clearly nothing anyone wants to do,” he added.

Antiretrovirals already reduce HIV to undetectable levels in the bloodstream, even though a person taking the drugs is not cured. To find lingering virus in a person taking anti-HIV drugs, scientists have to use painstaking methods to collect millions of blood and tissue cells and analyze them for residual HIV.

These methods are not practical for use on the general HIV-positive population, particularly since HIV will become rarer and harder to find as methods for eradicating it get better. As a result, many researchers think that HIV cure research will be hampered until a better way of detecting residual HIV reservoirs is found.

“One of the most important issues to address soon is how to quantify the size of the reservoir during therapy,” said Dr. Steven Deeks, a professor of medicine at the University of San Francisco, during the LiveChat. “The problem is that we have no ‘gold-standard’ to allow us to define which assay works the best.”

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during the LiveChat that development of a good test for residual HIV is a top priority for the agency.

“Developing a standardized assay to measure reductions in HIV viral reservoir is an important issue and we are hopeful that we will receive excellent proposals,” he said.

It is also possible that it is unnecessary to completely eliminate HIV from the body, that reducing it below a certain threshold will ensure HIV cannot rebound to cause a new infection. However, whether this is true, and if so, what that threshold is, are still unknown.

In the meantime, the definition of an HIV cure is likely to follow the path of cancer – people who show no evidence of the disease for a certain period of time, in the absence of antiretroviral drugs, would be declared cured.

“As in cancer, the term used is relapse-free survival,” said Dr. Margolis. “In the case of HIV, I think we must be satisfied with the result of no detectable HIV by advanced techniques in the absence of drug therapy.”

This is the definition that has been applied to “The Berlin Patient,” the only person cured of HIV so far. Doctors have failed to find HIV in his system after 45 months without antiretroviral therapy and have tentatively declared him cured of the virus, although they will continue to monitor him.

Practical Barriers: Laboratory Science And Clinical Trials

There are a number of other obstacles to a cure for HIV as well, some of which are solvable and some of which may not be. These include a need for better laboratory models for HIV, the time and expense of clinical trials, and the fact that it is impossible to tell which approach to a cure will be most successful.

“We are still in the process of discovery for a ‘cure.’ The discovery process is always unpredictable,” said Dr. Fauci.

Some of the problems facing HIV cure researchers are likely to improve over time. For example, one traditional barrier to cure research has been the fact that HIV is strictly a human disease – the virus has no effect on common laboratory research animals. Since researchers cannot conduct their research on humans, this presents challenges.

Scientists have gotten around this by using monkeys infected with Simian Immunodeficiency Virus (SIV), a close relative of HIV. Even this model of HIV is imperfect, since monkeys do not always react to SIV the same way humans do to HIV. In addition, until recently, treating monkeys with antiretrovirals was not successful, which means scientists could not use them to model HIV-infected humans taking anti-HIV drugs.

However, researchers more recently have been able to incorporate antiretrovirals by using SIV that has been genetically modified to contain HIV genes, making it susceptible to anti-HIV drugs. Although still not perfect, this allows for better and more accurate research into what HIV cure methods might be effective in people.

A number of other problems facing HIV researchers are more difficult to overcome. Clinical trials still take a lot of time and money, and this is not likely to change. There are also fears that efforts to cure HIV will not be supported by the major pharmaceutical companies, for whom antiretrovirals are often an important source of income.

However, many researchers are increasingly optimistic that a cure will be found in spite of these obstacles, and that pharmaceutical companies will also play an important role in cure research.

“I think many companies now realize that a cure is possible and that some profit can be made. There are a few companies (e.g., Merck and Gilead) that are making major investments. A number of other large companies are slowly and quietly moving in this direction,” said Dr. Deeks.

Funding efforts toward a cure have also increased as approaches look more promising.

“Recently, the International AIDS Society launched an international effort aimed at defining the barriers to a cure and raising the funds necessary to address these questions,” said Dr. Deeks.

“There has been significant progress [toward a cure] in the past year. Since the amount of funding is about to increase on a global level, I expect that the pace of advances will increase,” he added.

For more information, please see the review in the journal AIDS (abstract) or the Science LiveChat website. For more information about the potential for an HIV cure, please see Part 1 (general types of HIV cures), Part 2 (targeting latent HIV), and Part 3 (gene therapy and therapeutic vaccines) of this series.

Advances and Barriers To A Cure For HIV: Part 3 – Gene Therapy And Therapeutic Vaccines

April Clayton — Mon, 16 May 2011 10:00:24 +0000

This article is the third in a four-part series that will investigate current research toward finding a cure for HIV, including advances, promising treatment strategies, and barriers to reaching a cure. Part 1 discusses general types of HIV cures. Part 2 discusses specific strategies for targeting latent HIV. Part 3 discusses gene therapy and therapeutic vaccines. Part 4 discusses barriers to obtaining a cure.

As researchers become more optimistic that a cure for HIV will be found, they are pursuing a number of different possible strategies, including highly experimental techniques like gene therapy and therapeutic vaccines.

At this point, no one knows for sure what the most successful avenue to a cure will be.

“It took 10 years to get good ART [antiretroviral therapy], and another five to get really great ART. Eradication is likely to be harder. But we might find new tools from unexpected areas,” said Dr. Steven Deeks, a professor of medicine at the University of San Francisco who participated Thursday in a LiveChat on HIV cures on the Science Magazine website.

“Most of the activity is now in the laboratory. There have been a few recent clinical successes, however, including the bone marrow transplant case (the so-called ‘Berlin Patient’). This clinical study has energized the field. There are several ongoing clinical studies,” he added.

In a recent review, Dr. Sharon Lewin, director of the Infectious Diseases Unit at Alfred Hospital in Australia, and Professor Christine Rouzioux from the Université Paris Descartes in France discussed the possibility of gene therapy and therapeutic vaccines for providing a cure for HIV.

Using Gene Therapy To Make Cells Resistant To HIV

One of the most exotic and experimental methods being tested to cure HIV is gene therapy. Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying the genetic information in a cell so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In most cases, cells are taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

“There is intense interest in gene therapy,” said Dr. Deeks. “This interest is driven by the ‘Berlin Patient’ case as well as recent advances in gene therapy.”

The most advanced attempts at gene therapy so far are attempts to mimic the success of “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated form of the CCR5 gene.

In one recent high-profile Phase 2 gene therapy clinical trial, HIV-positive people on antiretrovirals were injected with modified immune cells lacking the CCR5 protein. The therapy did not eliminate HIV in these patients, but it did successfully raise CD4 counts in patients whose immune systems had failed to recover after starting antiretroviral therapy (see related AIDS Beacon news).

This approach is the most successful seen so far.

Another approach under investigation is an RNA-based gene therapy. This strategy works slightly differently but is also aimed at reducing or eliminating CCR5, as well as slowing HIV replication. In a recent study, scientists used this approach in HIV-positive individuals undergoing a blood stem cell transplant to treat AIDS-related lymphoma.

Results showed that the treatment was well tolerated and that the gene therapy was successful, although results faded after four weeks. Nonetheless, the study offered a proof-of-concept that RNA gene therapy is possible.

Dr. Deeks noted that, while gene therapy has potential, it may not be particularly practical in the long run. “This approach is not likely to be widely available on a global basis. Although I am enthusiastic about the gene therapy approaches, I think we really need to focus on safe and easy-to-administer interventions that can be used in resource-poor and -rich environments,” he said.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during the LiveChat that more results on gene therapy trials can be expected. “Stay tuned. You will be hearing further news soon about the funding of these types of studies,” he said.

Therapeutic Vaccines

Another experimental approach to finding a cure for HIV is the development of therapeutic vaccines. Therapeutic HIV vaccines work by enhancing the body’s natural immune response, helping to control HIV in people already infected with the virus. This is in contrast to preventative vaccines, which are used in HIV-negative individuals to prevent infection.

Researchers hope that therapeutic vaccines could be used to reduce or eliminate the need for HIV treatment. To date, the use of therapeutic vaccinations in HIV patients on antiretroviral therapy has not been successful.

However, results from two recent studies in Simian Immunodeficiency Virus (SIV)-infected monkeys have been promising. SIV is a retrovirus similar to HIV that infects primates; studying SIV can provide insight into potential therapies for HIV in humans.

In one study, monkeys were treated with antiretrovirals, a vaccine containing live but inactivated SIV virus, and a drug targeting the immune system. In the second, the monkeys were given a vaccine with a genetically modified version of cytomegalovirus (CMV) that had been designed to stimulate the immune system against SIV.

Results showed that monkeys in both trials had significant control of viral replication after receiving the vaccines; in the CMV study, half the monkeys achieved undetectable SIV levels.

Dr. Fauci stated during the LiveChat that he was optimistic about the implications of the recent CMV monkey study for the chances of a therapeutic vaccine.

“The ability of this [CMV] vector vaccine approach to suppress existing virus infection in such an effective way could play a major role in a ‘functional cure’ by allowing discontinuation of antiretroviral therapy, by inducing a potent enough immune response to keep the viral reservoir suppressed, although not eliminated,” he said.

Dr. Fauci also said that therapeutic vaccines are one of the NIAID’s first goals toward an HIV cure.

“My goal for HIV cure research in the short term (2011) is to pursue the arena of therapeutic vaccine trials to suppress virus rebound in the face of discontinuing of therapy,” he said.

“In the longer run (2012 and beyond), we are looking at developing and testing new classes of drugs that can eliminate reservoirs. Modified stem cells research is also a priority,” he added.

The Possible Future Of HIV Treatment – Part 2: Research Toward A Cure (CROI 2011)

April Clayton — Thu, 17 Mar 2011 19:34:09 +0000

This article is the second in a two-part series discussing Dr. Patrick Yeni’s presentation at the 18th Conference on Retroviruses and Opportunistic Infections, entitled “15 Years of HAART: What Does the Future Hold?” The first article discussed new antiretrovirals and treatments for HIV. The second article discusses ongoing research efforts to find a cure for HIV.

Although highly active antiretroviral therapy has improved greatly over the past 15 years, it does not cure HIV. As a result, researchers must continue to search for a way to cure HIV, either by completely eliminating the virus from the body or by controlling it without long-term use of antiretrovirals or other drugs, said Dr. Patrick Yeni, the head of infectious diseases at the Hospital Bichat Claude Bernard and a professor of medicine at the University of Paris, during a presentation at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

“This is necessary research because of the various limitations and constraints with antiretroviral therapy that probably will never be totally overcome,” said Dr. Yeni.

However, he noted that a cure for HIV is not likely in the near term.

“This is a long-term effort, and to what extent this effort will be successful in the future is impossible to tell now,” he said.

Dr. Yeni’s discussion on research into possible ways to cure HIV infection focused mostly on two methods: activation of latent HIV and gene therapy, both of which are still highly experimental.

Targeting Latent HIV Reservoirs

One method for possibly curing HIV is to remove cells infected with latent HIV. Latent HIV is HIV that is not actively replicating. Since antiretroviral drugs usually work by blocking replication, they do not work on latent HIV.

As a result, antiretrovirals can never fully remove HIV from the body. Latent HIV will activate if therapy is stopped, renewing the HIV infection.

Targeting this HIV involves activating it so that infected immune cells start producing HIV again. The HIV then kills the infected cells. At the same time, antiretroviral drugs prevent new cells from being infected. The result is that infected cells are killed off, leaving only uninfected cells behind.

Dr. Yeni mentioned several drugs that are being investigated as latent HIV activators. Different types of drugs target different pathways for activating latent HIV.

One type of drug that is under consideration is histone deacetylase (HDAC) inhibitors. HDAC inhibitors are currently used as mood stabilizers and anti-epileptic drugs; more recently, researchers have begun investigating them as anti-cancer treatments.

Zolinza (vorinostat), an HDAC inhibitor, is a drug currently approved to treat a type of lymphoma. Research has shown that Zolinza successfully activates latent HIV in infected cells in the laboratory. However, Dr. Yeni noted that it causes side effects when used long-term.

Prostratin, a chemical isolated from tree bark, is a traditional Samoan treatment for hepatitis. Researchers have found that it also activates latent HIV in the laboratory, although it works differently than HDAC inhibitors. Prostratin is still in pre-clinical studies.

Finally, researchers are also investigating the protein IL-7, which helps immune cells develop and survive, in a Phase 2 clinical trial to see if it can activate latent HIV when used with an intensified highly active antiretroviral (HAART) regimen.

Dr. Yeni cautioned that researchers still do not know precisely how HIV latency works or what the consequences of activating HIV might be. “There is a limited understanding of the mechanism of latency and the consequences of reversing latency,” said Dr. Yeni.

“These are gaps in knowledge that should be filled through active and coordinated basic research,” he added.

Gene Therapy

The second promising method that Dr. Yeni discussed for potentially curing HIV is gene therapy.

“The idea of HIV gene therapy emerged before HAART was available,” said Dr. Yeni. “Since that time, there has been considerable progress.”

Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying the genetic information in a cell so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In most cases, cells are taken from the patient’s body, genetically modified, and then injected back into the patient.

Dr. Yeni focused on current ongoing Phase 1 gene therapy clinical trials in which people with HIV are injected with modified immune cells lacking the CCR5 protein. People who naturally lack CCR5 are resistant to HIV infection.

Sangamo Biosciences, which runs the current Phase 1 gene therapy trials, released results at CROI showing that the therapy successfully raised CD4 counts in patients whose immune systems had failed to recover after starting antiretroviral therapy (see related AIDS Beacon news).

Dr. Yeni also mentioned a variety of other ongoing clinical trials that involve using gene therapy to prevent immune cells from being infected, to turn off HIV genes, or to enhance the immune system’s response to HIV using, for example, targeted vaccines.

However, he noted that gene therapy is not currently available for most people with HIV. “An essential question remains: how will gene therapy be adapted to become widely available in HIV-infected patients?” he asked.

For more information, please see the abstract or the webcast on the CROI 2011 website.

Gene Therapy May Increase CD4 Counts In People With HIV (CROI 2011)

Mariana Torrente — Wed, 02 Mar 2011 19:52:49 +0000

Results of a small Phase 1 clinical trial showed that gene therapy made cells of people with HIV resistant to HIV infection and increased CD4 counts. The results were presented Monday by Sangamo Biosciences at the 18th Conference on Retroviruses and Opportunistic Infections (CROI).

“While preliminary, these data are very encouraging and an early validation of the feasibility of our novel gene modification approach for the treatment of HIV/AIDS,” said Dr. Dale Ando, Sangamo’s vice president of therapeutic development and chief medical officer, in a press release.

Antiretroviral therapy has greatly increased life expectancy and improved quality of life for people with HIV. However, it does not cure HIV and often has side effects.

In addition, despite achieving low levels of HIV in the blood, some patients on antiretroviral drugs continue to have poor immune recovery and low CD4 (white blood cell) counts.

Gene therapy, an experimental approach that is currently in early stages of clinical testing, is a possible new treatment method that could one day provide a cure for HIV. Gene therapy involves modifying the genetic information in a cell to, for example, make it resistant to HIV.

In most cases, cells are taken from the patient’s body, genetically modified, and then injected back into the patient.

In the Sangamo trial, carried out jointly with investigators at the University of California at Los Angeles and San Francisco, investigators genetically modified immune cells, called T-cells, to remove a protein called CCR5.

The researchers hoped that T-cells, including CD4 cells, in which CCR5 is removed would be immune to the virus and thus able to block viral entry and replication. They also hoped the cells would multiply to make other HIV-resistant T-cells.

The study included six HIV-positive adults on antiretroviral therapy with CD4 counts between 200 and 500 cells per microliter. All the participants had successfully achieved undetectable levels of HIV while on therapy, but had not experienced a sufficient recovery in their CD4 counts.

The researchers collected immune cells from participants, genetically modified them, then reinjected the cells. Patients were monitored weekly for one month and then monthly for 11 months post-treatment.

Results showed that a single treatment with the modified cells resulted in significant and durable CD4 increases in five out of the six participants.

Two weeks after the injection, CD4 counts increased in the five participants by 35 to 1,038 cells per microliter. After a year, CD4 counts had increased by 86 to 911 cells per microliter in these five participants.

The researchers did not observe any lasting improvements in CD4 counts from the procedure in the sixth study participant.

Results also showed that the modified cells exhibited normal growth and activity.

The treatment was well tolerated. The researchers did not observe any major side effects.

The clinical trial is ongoing and is still recruiting participants in Los Angeles and San Francisco; eligible participants must have been on antiretroviral therapy for at least two years and have CD4 counts between 200 and 500 cells per microliter.

Sangamo has recently decided to expand the trial to include people whose antiretroviral therapy has not been effective in suppressing the virus. Total expected enrollment for the trial is 13 participants.

In addition, a second similar gene therapy clinical trial by Sangamo Biosciences is currently underway in Philadelphia and New York City.

This trial is recruiting three groups for treatment: people for whom two or more antiretroviral therapy regimens have failed to effectively control the virus, with viral loads of 2,000 copies per milliliter or higher and CD4 counts of at least 200 cells per microliter; people with successful antiretroviral regimens and undetectable viral loads; and people whose treatment regimens have successfully suppressed their viral loads to undetectable levels but who still have low CD4 counts, less than 500 cells per microliter of blood, after two or more years of treatment.

The researchers expect to enroll around 18 participants.

For more information, please see the press release by Sangamo Biosciences or the abstract at the CROI 2011 website.

Beacon NewsFlashes – December 20, 2010

Courtney McQueen — Mon, 20 Dec 2010 19:03:15 +0000

Bristol-Myers Squibb Licenses Prospective Anti-HIV Drug Festinavir – Bristol-Myers Squibb announced today that it has licensed the prospective new anti-HIV drug festinavir from Oncolys BioPharma, a small Japanese pharmaceutical company. Festinavir is a once-daily nucleoside reverse transcriptase inhibitor (NRTI) that is currently in Phase 2 clinical trials. Results from Phase 1 trials indicate the drug may have fewer side effects than currently approved NRTIs. The agreement gives Bristol-Myers Squibb international rights to manufacture, develop, and sell the drug. For more information, please see the Bristol-Myers Squibb press release.

German Doctors Report Man Cured Of HIV With Unusual Bone Marrow Stem Cell Treatment – Researchers in Germany announced last week that the man known as “the Berlin patient,” an HIV-positive man who received an unusual bone marrow stem cell transplant to simultaneously treat his leukemia and cure his HIV, remains free of HIV three years after the transplant. The treatment was unusual because doctors were able to find a stem cell donor who also had a rare mutation that confers immunity to HIV. The results were first reported in 2008, but there was concern that his HIV might reappear eventually. The report last week indicates that after three years there is still no sign of HIV infection. Other researchers and doctors have warned that the treatment was risky and not suitable for general use; however, it does indicate that gene therapy, an experimental form of treatment that allows researchers to add or remove genes, may offer a way of curing HIV. For more information, please see the Associated Press article. For a “Frequently Asked Questions” page about the German patient’s HIV cure and its implications for people with HIV, please see the WebMD website.

Clinical Trial On Higher Flu Vaccine Dose Is Currently Recruiting Participants – A clinical trial that will test a higher dose of the flu vaccine in people with HIV is currently recruiting participants in Philadelphia. The trial aims to determine if the Fluzone High Dose vaccine will elicit a better immune system response and therefore better protection against the influenza virus in people with HIV. Fluzone High Dose is a new flu vaccine made by Sanofi-Aventis that is designed for people ages 65 and older, who naturally have weaker immune systems. Eligible trial participants must be 18 years or older and either on a stable antiretroviral regimen or not taking antiretrovirals with no plan to begin treatment within 30 days of starting the trial. For more information, please see the United States Clinical Trials Registry. For more information on Fluzone High Dose, please see the Centers for Disease Control website.

http://www.bms.com/news/press_releases/pages/default.aspx

New Report Finds A Variety Of New HIV Drugs And Vaccines Under Development

Courtney McQueen — Tue, 14 Dec 2010 17:57:28 +0000

United States pharmaceutical companies have a total of 40 new antiretrovirals, three possible gene therapy treatments, and several therapeutic vaccine candidates under development for treatment of HIV, according to a new report from the Pharmaceutical Research and Manufacturers of America.

The Pharmaceutical Research and Manufacturers of America (PhRMA), a pharmaceutical company lobbying group, releases a report each year on HIV treatments under development at U.S. pharmaceutical companies. The report this year includes new antiretrovirals, gene therapies, and vaccine candidates, in addition to treatments for HIV-related conditions such as Kaposi’s sarcoma and peripheral neuropathy (pain or numbness in the extremities).

Most of the new antiretrovirals are still in Phase 1 or Phase 2 clinical trials. The list includes novel drug types that work differently than current anti-HIV drugs, as well as drugs in standard antiretroviral drug classes, such as new protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs).

In addition, there are three new combination treatments under development. Combination treatments include several antiretrovirals in one pill, which simplifies treatment regimens.

New Types Of Antiretroviral Drugs

Several of the antiretrovirals in the report are novel drug types that are not part of existing antiretroviral drug classes.

A number of these treatments consist of antibodies, proteins that help the body recognize and fight viruses. These treatments usually work by attempting to stimulate the immune system so that it can more effectively recognize and kill HIV or infected cells. Nearly all of these are still in Phase 1 clinical trials, although one set of antibodies are in Phase 2 trials.

There are a few additional prospective drugs that have made it to Phase 2 trials. One of these is also a protein treatment, called Alferon LDO (interferon alfa-n3). This protein is isolated from human blood and helps fight viral infections; currently it is approved by the U.S. Food and Drug Administration to fight human papillomavirus, which causes genital warts.

Another new treatment, called CB1922, is currently in Phase 2 clinical trials. CB1922 is a drug that has mostly been investigated for treatment of high blood pressure. It works by blocking a protein on the surface of cells that normally binds to a hormone called aldosterone.

Canopus BioPharma, which makes CB1922, has found that HIV also binds to this same protein by mimicking the hormone. By blocking the protein, CB1922 appears to prevent HIV from replicating itself.

Finally, a drug from Bristol-Myers Squibb, called BMS-626529, is also in Phase 2 clinical trials. Bristol-Myers Squibb has not explained the mechanism of BMS-626529, but states that it prevents HIV from attaching to cells, which would prevent infection and virus replication.

New Drugs In Existing Antiretroviral Drug Classes

Most of the new drug candidates are in existing antiretroviral drug classes, including the following two drugs that are in or have completed Phase 3 trials: elvitegravir, which is a new integrase inhibitor from Gilead Sciences, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Tibotec Pharmaceuticals.

Integrase inhibitors, such as elvitegravir, are a relatively new class of antiretroviral; currently, the only approved integrase inhibitor is Isentress (raltegravir).

In addition to elvitegravir, there are three new integrase inhibitors under development (GSK1247303, GSK1265744, and GSK1349672). All of these are in Phase 2 clinical trials and were developed by GlaxoSmithKline.

NNRTIs, in contrast, are an older drug class that includes Sustiva (efavirenz), Viramune (nevirapine), and Intelence (etravirine). Including rilpivirine, there are seven new NNRTIs under development; four of these are also in Phase 2 clinical trials (dapivirine vaginal gel, RDEA806, UK-453061, and VRX806).

The list includes seven new NRTIs, which is the oldest antiretroviral drug class and includes drugs such as zidovudine (Retrovir) and Epivir (lamivudine). Four of the proposed new NRTIs (elvucitabine, festinavir, racivir, and amdoxovir) are in Phase 2 clinical trials.

Only two new protease inhibitors (a drug class that includes Prezista (darunavir) and Kaletra (lopinavir/ritonavir)) were included in the report, one of which, TMC310911, is in Phase 2 trials.

Finally, the report includes several new entry inhibitors, which are another fairly new class of antiretroviral that includes the drugs Selzentry (maraviroc) and Fuzeon (enfuvirtide).

Entry inhibitors work by preventing HIV from entering and infecting new cells. Most of the new treatments act the same way as Selzentry, which blocks a protein called CCR5 on the surface of white blood cells that HIV uses to attach to and invade. Two of the proposed new entry inhibitors (PRO-140 and TBR-652) are in Phase 2 clinical trials.

New Combination Drugs

Combining several antiretroviral drugs into one pill has been a growing trend, since it simplifies antiretroviral regimens for patients. There are currently three combination treatments under development.

One, called the “Quad” pill (see related AIDS Beacon news), is a combination of four drugs in one pill: Emtriva (emtricitabine), Viread (tenofovir), and the investigational integrase inhibitor elvitegravir plus a proposed new antiretroviral booster, cobicistat. Cobicistat is thought to act similarly to Norvir (ritonavir) by raising antiretroviral drug concentrations to make them more effective.

A second combination pill will include the new NNRTI rilpivirine plus Emtriva and Viread.

Finally, the third proposed combination pill will include three already approved antiretrovirals: Sustiva (efavirenz), Epivir (lamivudine), and Viread.

Gene Therapy And Vaccines

Aside from antiretroviral drugs, the report includes both gene therapies and therapeutic vaccine treatments as potential new HIV treatments.

Gene therapy treatments are experimental procedures that scientists hope will one day be able to cure HIV (see related AIDS Beacon news). They work by changing a person’s genes, for example by turning off genes that produce proteins used by HIV to infect cells.

Three gene therapy treatments are currently under development, two of them in Phase 1 trials and one in Phase 2.

Two of the treatments work by inserting genes that make genetic material that binds to and neutralizes HIV’s genetic material so that it no longer functions. One of the treatments is being developed by the biotechnology company VIRxSYS and is currently in Phase 1 trials. The second one by Enzo Biochem is currently in Phase 2 trials.

The third therapy, by Sangamo Biosciences, works by preventing cells from producing the CCR5 protein on their surface, preventing HIV from infecting the cells in much the same way Selzentry does.

Finally, there are a number of therapeutic vaccines also under development (see related AIDS Beacon news). Therapeutic vaccines enhance the body’s natural immune response, helping to control HIV in people already infected with the virus.

Most of the therapeutic vaccines are in Phase 1 clinical trials. However, there are a few that are in Phase 2.

One of these is a dendritic cell vaccine by Argos Therapeutics. Dendritic cell vaccines are made by collecting blood from patients and isolating a certain type of immune cell called a dendritic cell.

After exposing the dendritic cells to HIV proteins in the laboratory to prompt an immune response, the cells are reinjected into the study participant in hopes that the cells will now be activated and fight against HIV.

Two other therapeutic vaccines that are in Phase 2 clinical trials are the DermaVir vaccine, by the company Genetic Immunity, and Vacc-4x by Bionor Pharma (see related AIDS Beacon news).

The DermaVir vaccine is applied as a patch rather than an injection and attempts to limit virus replication. Vacc-4x, in contrast, contains protein fragments similar to those found within the HIV virus, in an attempt to enhance the ability of patients’ immune systems to recognize and kill HIV-infected cells.

For more information, please see the report from PhRMA. For more information on clinical trials, please see the United States Clinical Trials Registry.