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Gene Therapy? (GENE THERAPY, 2009)

Jun 16, 2009

Hi Dr. Bob, Could you discuss recent discoveries in stem cell transplants and gene therapy? It seems very promising. I have read some things about it, but it is never covered in any of the information in The Body.

Response from Dr. Frascino


Gene therapy and stem cell transplants never get covered in any of the information on The Body? Really??? Hmm . . . see below for a small sample of what's available.

Dr. Bob

gene therapy via blood stem cells new treatment for hiv ??? Jun 7, 2009

Hi Dr Bob,

l am recently infected with hiv and guess what you have become my hero, please keep up the great work you do for us hivers around the world, l read all your posts and you are the man period... l need to start treatment asap cd4 300 and viroal load 85,000k.... but l have been reading about this blood stem cell treatment via gene therapy,

look l know treatment like this are at least a hope for us to try and live a normal life without meds,

Dr Bob get the crystel ball out the same one in the harry potter film and find out when can we sometime in the future get started on this cutting edge treatment,keep up the great work, you are a very special person.....



Gene Therapy Holds Promise for HIV But research is preliminary and more trials are needed, study says Posted February 15, 2009 By Randy Dotinga HealthDay Reporter

SUNDAY, Feb. 15 (HealthDay News) -- Researchers are reporting promising results from the largest clinical trial of gene therapy for HIV patients. The findings, while encouraging, need to be replicated and more research must be done before an effective new treatment arrives, experts said.

People Who Read This Also Read Many Hospital Patients Can't ID Their Doctors 21983311 Love and Romance: Get the Health Benefits Even if You're Single 21983693 Recent HIV News Is Encouragingbut Also Provides Cause for Concern 21955837 Add More Facts to Drug Ads, Experts Urge 22045400 A Caution About Rapid HIV Testing 20194973 "We know it works, but we need to make it better before we launch a later study," said study lead author Dr. Ronald Mitsuyasu, director of the University of California, Los Angeles Center for Clinical AIDS Research and Education.

Existing treatments work fairly well for many people with HIV, the virus that causes AIDS. But patients have to take expensive drugs for their entire lives, and side effects can be significant.

Gene therapy is considered a possible alternative to drug treatment. Researchers hope to fight the virus by inserting a gene or genes into the body of an infected individual.

Last week, the New England Journal of Medicine reported a case that showed the potential for gene therapy and HIV. According to the journal, the body of a man in Germany with AIDS became free of the virus after he received a bone marrow transplant from a man with a gene that made him virtually immune to HIV. The treatment may not be a cure because the AIDS virus can become undetectable while still remaining in the body.

In the new study, researchers focused on a molecule that targets the AIDS virus. The scientists recruited 74 HIV-positive people and intravenously gave them either the molecule -- called OZ1 -- via blood stem cells, or a placebo. The patients then cycled on and off their HIV drugs so the researchers could see if the virus rebounded.

The patients who got the gene therapy treatment had a "modest decline" in the level of virus in their bodies, Mitsuyasu said. After 100 weeks, immune systems were also stronger in those patients who received the gene therapy vs. those who did not. In fact, some patients are doing so well that they haven't returned to drug treatment, Mitsuyasu said.

The findings were published online Feb. 15 in the journal Nature Medicine.

The study was a "phase II" trial, meaning that a third study would be necessary before the treatment could be approved.

There's more to be done, however, Mitsuyasu said.

"We need to figure out how best to perfect this approach. There are a lot of things that we could potentially do," he said. But in the big picture, the research represents "the first clear indication in a randomized and controlled study that there is a biologic effect of gene therapy" for HIV, he added.

The new approach holds promise, said Rowena Johnston, vice president of research at the Foundation for AIDS Research (amFAR) in New York City.

"One of the striking successes of this particular approach is its apparent safety, which is no small matter given the history so far of gene therapy interventions," she said. "Gene therapy will probably represent an exciting new frontier that will receive increasing attention in the coming years. There are so many unexplored avenues to pursue with the real potential to provide a lasting solution for HIV/AIDS."

More information

To learn more about gene therapy, visit the Human Genome Project Information

Response from Dr. Frascino

Hello Pat,

Thanks for your kind comments.

The results of the OZ1 stem cell gene therapy phase II clinical trial were exciting and encouraging in equal measure. Dr. Ron Mitsuyasu at UCLA is an excellent HIV/AIDS/oncologist physician specialist who has been conducting cutting edge immune-based HIV research for quite some time. (He's also a good friend of mine!) His comment that this study is "the first clear indication in a randomized and controlled study that there is a biological effect of gene therapy" for HIV should help in getting funding and approval for additional HIV-related gene therapy clinical trials. This study was encouraging but not a "homerun," as the treatment group only experienced a "modest decline" in HIV plasma viral load. However, there was evidence that the treatment group had sustained (out to 100 weeks) strengthening of a number of immune parameters. This type of immune-based therapy is exactly what's needed, in my opinion, to work with our antiretrovirals (or ideally in place of the antiretrovirals!). As for when this type of therapy will be read for primetime, unfortunately even Professor Trelawney's crystal ball can't predict. What we can say is that it's still quite a ways off (years). However, for now we should celebrate a major step forward with a big collective WOO-HOO!!!

I'll keep you posted on this as other promising treatment stories continue to evolve.

Be well Pat! Let's all be here for the cure, OK?

Dr. Bob

Gene Therapy trials starting soon... Apr 11, 2009

Hi Dr Robert, please keep up the great work you do for hivers....

l live in sydney and have been hiv positive for 6 years my age now is 37 years old,

l have put my hand up for a new phase gene therapy trail starting at st vincents hospital...

The person behind the trial is Thomas Merigan MD, l have read where the first trail which started in 2004 and finshed in 2008 was safe and had good to modest results...

can you please tell more about the benefits of gene therapy ???

thank you for your time

Response from Dr. Frascino


Gene therapy is a rapidly growing field of medicine that involves the introduction of genes (and sometimes specifically altered genes) into the body to treat certain diseases. There are several studies underway in the field of HIV research. I don't have specific information on the exact trial you are referring to, but the HIV specialists running the clinical trial should be able to give you a very complete explanation of both the potential risks and benefits of participating in the trial. I'll reprint some information below from the archives that pertains to the subject.

Good luck.

Dr. Bob

genetically engineer immune cells into potent weapons for battling HIV (CTL, GENE THERAPY) Mar 7, 2008

I would love to know what you think about this.................Einstein researchers genetically engineer immune cells into potent weapons for battling HIV March 4, 2008 (Bronx, NY) By outfitting immune-system killer cells with a new pair of genes, scientists at the Albert Einstein College of Medicine of Yeshiva University transformed them into potent weapons that destroy cells infected with HIV, the virus that causes AIDS. Their novel strategy of genetically engineering immune cells to redirect their infection-fighting ability toward killing HIV-infected cells could lead to an entirely new approach for combating AIDS and other viral diseases. The findings appear in the March issue of the Journal of Virology.

After someone is infected with HIV, a subgroup of their immune cells known as CD8 cytotoxic T lymphocytes, or CTLs, recognize cells infected with HIV and kill them before they become HIV-producing factories. This CTL activity initially keeps the infection in check.

But thenlargely because these CTLs may not bind tightly enough to the infected cells or because HIV mutates so rapidlythe virus typically evades and ultimately overpowers the immune system, leading to an increase in viral load that, in the absence of drug therapy, results in AIDS. However, a very small percentage of HIV-infected people known as elite controllers manage to suppress HIV infection for many years.

Certain of the CTLs of elite controllers may be genetically equipped to bind tightly to HIV-infected cells and destroy them and thereby suppress the infection indefinitely, says Dr. Harris Goldstein, senior author of the study and Director of the Einstein/Montefiore Center for AIDS Research. Our idea, says Dr. Goldstein, was first to identify the elite controllers super CTLs and to isolate the genes that enable these cells to bind tightly to HIV-infected cells and kill them efficiently; then we would transfer these genes into CTLs that do not recognize HIV-infected cells and convert them into potent killers of those cells.

After infecting a cell, HIV instructs it to make viral proteins. Tiny bits of these proteins, known as peptides, are displayed on the surface of the infected cellthe cells way of signaling the immune system that it is infected. Detecting virus-infected cells so they can then be eliminated is the job of CTLs and the protein molecules, known as T-cell receptors, that jut from their surface.

If a CTLs T-cell receptor has the right amino acid sequence, it will recognize the HIV peptide on the infected cell as foreign--prompting the CTL to multiply and attack the infected cell. But all too often, this battle between activated CTLs and HIV-infected cells ends badly. Why, then, are super CTLs of elite controllers so effective in killing HIV-infected cells"

The explanation, the Einstein researchers postulated, is that these CTLs express T-cell receptors that either have a knack for recognizing viral peptides that tend not to mutate, or they bind extremely tightly to HIV-infected cells, enabling the elite controllers to keep their HIV infections under control.

A CTLs T-cell receptor, which is as unique for each CTL as a persons fingerprint, consists of two chains, alpha and beta. To obtain the blueprint for making exceptionally potent HIV-specific T-cell receptors, the researchers isolated the genes that code for each of the two chains from the potent HIV-specific CTL. Then, as a way to efficiently insert both genes into nave CTLs (from people not infected with HIV), they developed an efficient delivery system in which the genes were combined and packaged inside a special type of virus, called a lentivirus. The lentiviruses then inserted these genes into the chromosomes of nave CTLs obtained from a nave donors blood and reprogrammed them into potent HIV-specific CTLs.

We demonstrated that these genetically reprogrammed CTLs have very strong activity in terms of killing HIV-infected cells in both test tubes and an animal model, says Dr. Goldstein. In some of the animal studies, for example, the researchers injected mice with both HIV-infected human cells and with reprogrammed nave CTLs into which the HIV-recognizing T-cell receptor genes had been inserted using the lentiviral delivery system. One week later, when the researchers looked for HIV-infected human cells in the animals, they found that the infected cells had virtually been eliminated.

Dr. Goldstein notes that this study was done using genes for just a single CTL T-cell receptor. To make this strategy even more effective, were now in the process of isolating a cocktail of CTL receptor genes that are specific for many different HIV peptidesan approach analogous to todays combination drug therapy for treating HIV infection, says Dr. Goldstein. Ultimately, wed like to remove CTLs from patients, convert them into potent HIV-specific CTLs by inserting a variety of HIV-specific CTL receptor genes, and then re-infuse these fresh, genetically reprogrammed CTLs back into patients. By reinforcing the immune system in this way, we hope to turn the tide of battle against HIV in favor of people infected with the virus.

Response from Dr. Frascino


This is extremely interesting and important work. As an immunologist, I have advocated immune-based therapies for HIV treatment and, ultimately, cure since the early days of the epidemic. It's becoming clearer that despite truly remarkable progress in the development of antiretroviral drugs, ultimately we need something else to help us reach the holy grail of "cure!" Immune-based therapy holds the most promise. The report you cited involves gene therapy, which is perhaps the most promising and, unfortunately, the most challenging type of immune-based therapy. The immune system is exquisitely balanced and phenomenally complex. Every time we tinker with one small aspect of it unintended consequences are set off elsewhere in the system. To provide an analogy, using our current scientific tools and techniques to genetically fix a problem involving the immune system is a bit like using only a sledgehammer to tune up your Maserati's engine. No doubt we are making great strides in genetic engineering and in achieving a better understanding of the immune-based pathophysiology of HIV. I too believe the elite controllers may well hold the key to ultimately unlocking this mystery. The research you quote is fascinating and certainly worth pursuing, but don't look for genetically engineered CTLs to show up on the pharmacy shelves at your local Piggly Wiggly anytime soon. This is very preliminary stuff and has only been investigated in "Mickey and Minnie." When it comes to genetics and illness, the significant differences "of mice and men" are well known. Just ask Steinbeck!

We'll all be following this CTL story and promise to keep you updated as further information becomes available.

Dr. Bob

Gene Therapy Apr 18, 2006

Hi Dr, Bob

What do you think about gene therapy ? The San Francisco Chronicle reported that Gene therapy has promissing result I just like to hear from an expert like you thanks Doc


Response from Dr. Frascino


I assume you are referring to the gene therapy clinical trial currently underway in San Francisco, Los Angeles and Sydney. For our readers unfamiliar with this study, I'll briefly explain. The 74 clinical trial participants first spend 16 hours hooked up to a machine that filters out stem cells and returns the rest of the blood to the body. This is called aphoresis. Next, the harvested stem cells are infected in the laboratory with a harmless mouse virus specifically engineered to carry the ribozyme gene. These genes are genetic blueprints that tell the cell how to make the enzyme ribozyme. Ribozyme is a custom-built chemical "scissors" that cuts up one of HIV's nine genes just as the virus tries to replicate itself. Three days after the gene is transferred into the stem cells, these genetically altered stem cells are returned to the patient's bloodstream. In subsequent weeks, these gene-modified stem cells produce a variety of infection-fighting white blood cells, each containing the ribozyme that we hope will be able to ward off HIV. If all goes according to plan, when HIV tries to infect these fortified blood cells, the virus will be destroyed. Ultimately we may even be able to rebuild or reconstitute the HIV-damaged immune system.

As you can see, this is very high-tech stuff. One of my good friends, Dr. Ron Mitsuyasu, director of the UCLA Center for Clinical AIDS Research and primary investigator on this clinical trial in Los Angeles, collaborated with the Australian team on the first pilot study of the new therapy, showing it was safe. None of us, including Dr. Mitsuyasu, believes this complex therapy will replace effective antiretroviral drugs. However, studies like these are opening new avenues of research that allow us to explore ways of using the immune system, gene therapy and stem-cell therapy in combination to work towards our ultimate goal a cure for HIV.

Stay tuned to this site, Tony. We'll keep you updated as this and other immune-based-therapy stories evolve.

Dr. Bob

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