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Stem cell gene therapy for sickle cell disease advances toward clinical trials

By Stell Cell Research

July 1, 2013 Researchers at UCLA's Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research have successfully established the foundation for using hematopoietic (blood-producing) stem cells (HSC) from the bone marrow of patients with sickle cell disease (SCD) to treat the disease. The study was led by Dr. Donald Kohn, professor of pediatrics and microbiology, immunology and molecular genetics in the life sciences.

Kohn introduced an anti-sickling gene into the HSC to capitalize on the self-renewing potential of stem cells and create a continual source of healthy red blood cells that do not sickle. The breakthrough gene therapy technique for sickle cell disease is scheduled to begin clinical trials by early 2014. The study was published online in the Journal of Clinical Investigation.

Gene Therapy

Kohn's gene therapy approach using HSC from patient's own blood is a revolutionary alternative to current SCD treatments as it creates a self-renewing normal blood cell by inserting a gene that has anti-sickling properties into HSC. This approach also does not rely on the identification of a matched donor, thus avoiding the risk of rejection of donor cells. The anti-sickling HSC will be transplanted back into the patient's bone marrow and multiplies the corrected cells that make red blood cells without sickling.

"The results demonstrate that our technique of lentiviral transduction is capable of efficient transfer and consistent expression of an effective anti-sickling beta-globin gene in human SCD bone marrow progenitor cells, which improved the physiologic parameters of the resulting red blood cells." Kohn said.

Kohn and colleagues found that in the laboratory the HSC produced new non-sickled blood cells at a rate sufficient for significant clinical improvement for patients. The new blood cells survive longer than sickled cells, which could also improve treatment outcomes. The success of this technique will allow Kohn to begin clinical trials in patients with SCD by early next year.

Sickle Cell Disease

Affecting more than 90,000 patients in the US, SCD mostly affects people of Sub-Saharan African descent. It is caused by an inherited mutation in the beta-globin gene that makes red blood cells change from their normal shape, which is round and pliable (like a plastic bag filled with corn oil), into a rigid sickle-shaped cell (like a corn flake). Normal red blood cells are able to pass easily through the tiniest blood vessels, called capillaries, carrying oxygen to organs such as the lungs, liver and kidneys. But due to their rigid structure, sickled blood cells get stuck in the capillaries and deprive the organs of oxygen, which causes organ dysfunction and failure.

Current treatments include transplanting patients with donor HSC, which is a potential cure for SCD, but due to the serious risks of rejection, only a small number of patients have undergone this procedure and it is usually restricted to children with severe symptoms.

CIRM Disease Team Program

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Stem cell gene therapy for sickle cell disease advances toward clinical trials

Stem-cell cocktail produces human liver tissue in mice

By Stell Cell Research

Published: Wednesday, July 3, 2013, 6:42p.m. Updated: Wednesday, July 3, 2013

An international stem cell research team reported on Wednesday that they have grown functioning human liver tissues in mice.

The human liver buds implanted in the mice represent a first experimental step in growing replacement organs from stem cells for transplants, such as liver, pancreas and kidneys, says the research team headed by Japan's Takanori Takebe of the Yokohama City University Graduate School of Medicine. The team relied on a cocktail of so-called induced stem cells grown to resemble the nascent liver bud cells used in the experiment.

The liver bud is formed at the very early stage of development normally in humans, maybe around five or six weeks, Takebe said. We basically mimicked this very early transition process of the liver-bud-forming process.

Discovered in 2006, induced stem cells are grown from mature tissues, typically skin cells, into the unspecialized stem cell state that allows for their cultivation into a wide variety of cell types, from brain to blood to liver cells.

Implanted into mice, the liver buds released human liver enzymes much more effectively than more copious amounts of liver precursor cells implanted alone in mice. The buds also developed blood vessels and grew to resemble normal liver tissues within about two days of implantation. As a final test, the researchers induced a kind of chemically induced liver failure that resembles the disease in people in 12 of the mice, and they report that implanted liver buds helped the mice survive.

Despite the effort's success, Takebe warned that implants of such tissues in human patients are at least a decade away, after tests of their long-term growth and safety.

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Stem-cell cocktail produces human liver tissue in mice

Stem-cell therapy wipes out HIV in 2 patients

By Stell Cell Research

LONDON - Two men with HIV have been off AIDS drugs for several months after receiving stem-cell transplants for cancer that appear to have cleared the virus from their bodies, researchers reported on Wednesday.

Both patients, who were treated in Boston and had been on long-term drug therapy to control their HIV, received stem-cell transplants after developing lymphoma, a type of blood cancer.

Since the transplants, doctors have been unable to find any evidence of HIV infection, Timothy Henrich of Harvard Medical School and Brigham and Women's Hospital in Boston told an International AIDS Society conference in Kuala Lumpur.

While it is too early to say for sure that the virus has disappeared from their bodies altogether, one patient has now been off antiretroviral drug treatment for 15 weeks and the other for seven weeks.

Last July Henrich first reported that the two men had undetectable levels of HIV in their blood after their stem-cell treatment, but at that time they were still taking medicines to suppress HIV.

Using stem-cell therapy is not seen as a viable option for widespread use, since it is extremely expensive, but the latest cases could open new avenues for fighting the disease, which infects about 34 million people worldwide.

The latest cases resemble that of Timothy Ray Brown, known as "the Berlin patient", who became the first person to be cured of HIV after receiving a bone marrow transplant for leukaemia in 2007. There are, however, important differences.

While Brown's doctor used stem cells from a donor with a rare genetic mutation, known as CCR5 delta 32, which renders people virtually resistant to HIV, the two Boston patients received cells without this mutation.

"Dr. Henrich is charting new territory in HIV eradication research," Kevin Robert Frost, chief executive officer of the Foundation for AIDS Research, which funded the study, said in a statement.

Scientific advances since HIV was first discovered more than 30 years ago mean the virus is no longer a death sentence and the latest antiretroviral AIDS drugs can control the virus for decades.

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Stem-cell therapy wipes out HIV in 2 patients

New stem cell patent action filed

By Stell Cell Research

A patent controlling use of human embryonic stem cells should be struck down, two consumer groups said in a legal appeal filed Tuesday.

Promising therapies developed with these cells will be delayed from reaching patients if the patent remains intact, say researchers, including Jeanne Loring of The Scripps Research Institute and Gene Yeo of UC San Diego.

The appeal was filed by Consumer Watchdog, based in Santa Monica, and the New York-based Public Patent Foundation, with the U.S. Court of Appeals. The groups said the U.S. Patent and Trade Office incorrectly upheld a patent awarded to the Wisconsin Alumni Research Foundation.

WARFs use of what is called the 913 patent, has put a severe burden on taxpayer-funded research in the State of California, the appeal stated. The California Institute for Regenerative Medicine funds embryonic and nonembryonic stem cell research with $3 billion from state bonds.

CIRM's president, Dr. Alan Trounson, did not directly say whether the California Institute for Regenerative Medicine supported or opposed the new filing.

"We don't want to do anything that gets in the way of finding treatments for some of the biggest killers today, so we feel that all patients with all kinds of diseases deserve to have access to these kinds of cells," Trounson said.

Yeo said the foundation permits basic research with embryonic stem cells, but warns scientists that any products resulting from that research requires a license. This warning scares away potential corporate partners.

Last months Supreme Court decision invalidating gene patents held by Myriad Genetics makes the case especially timely, the groups said in their brief. Human embryonic stem cells are a product of nature like genes, and so cannot be patented, they say. In addition, isolating those cells is an obvious extension of their discovery in other animals. The Public Patent Foundation and the ACLU represented those challenging Myriad's patents.

The case began in 2006, when stem cell scientists joined the two groups in challenging the WARF patent and two others. The other two have been dropped from the litigation. Loring took part in the original challenge and continues to advise the groups. The 913 patent is the most troublesome, because of its broad scope, Loring said.

The foundation said it was properly protecting breakthrough research from the University of Wisconsin at Madison by James Thomson. In 1998, Thomson was the first to isolate and culture human embryonic stem cells, which had previously been found in other animals.

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New stem cell patent action filed

Scientists create human liver from stem cells

By Stell Cell Research

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Scientists create human liver from stem cells

No trace of HIV after stem-cell transplants, researchers say

By Stem Cell Treatment

By Dennis Thompson HealthDay Reporter

WEDNESDAY, July 2 (HealthDay News) -- Two HIV-positive patients show no trace of virus after receiving chemotherapy and stem-cell transplants as treatment for lymphoma, according to new research.

These patients have become the second and third known cases of a "sterilizing cure," in which medical treatment removes all traces of HIV -- the virus that causes AIDS -- from the body. They have remained virus-free even though doctors months ago took them off their HIV-targeted medications.

"We have been unable to detect virus in either the blood cells or the plasma of these patients," said lead researcher Dr. Timothy Henrich, of Harvard Medical School and Brigham and Women's Hospital in Boston. "We also biopsied gut tissue from one of our patients, and we were unable to detect HIV in the cells of the gut. Essentially, we do not have any evidence of viral rebound."

The findings are scheduled for presentation Wednesday at the International AIDS Society Conference in Kuala Lumpur, Malaysia.

The patients had been receiving long-term antiretroviral therapy for HIV when they developed lymphoma, a type of blood cancer involving white blood cells, Henrich said.

Both underwent chemotherapy followed by bone marrow transplants to cure their lymphoma. Afterward, Henrich could not detect any HIV infection in their bodies.

Henrich presented preliminary findings on the research at the International AIDS Conference last July. Since then, he and his research team withdrew the patients' antiretroviral therapy to see how completely the cancer treatment had rid them of HIV. One patient has been off treatment with no detectable virus for about 15 weeks, and the second patient for seven weeks.

Henrich warned that it is too soon to declare the patients completely cured of HIV. "Although we cannot detect HIV, it's possible it's there but in extremely low amounts," he said. "We're going to watch and wait, and see where it goes with these patients."

Unfortunately, this type of cure is not something that can be put into widespread practice for all people infected with HIV. "Transplantation is not a scalable, affordable or even safe treatment for HIV patients," Henrich said.

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No trace of HIV after stem-cell transplants, researchers say

Two stem cell transplant recipients now controlling HIV off treatment

By Stem Cell Treatment

Two people with HIV who received stem cell transplants for the treatment of lymphoma are now controlling HIV replication without medication in the early weeks of treatment interruption, following the discovery that both had experienced loss of detectable HIV DNA, researchers from Boston reported on Wednesday at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

Although the treatment patterns of the two patients bear some similarities to the 'Berlin patient' who experienced a 'functional cure' of HIV infection after aggressive chemotherapy, immunosuppressive treatment and a bone marrow transplant from a donor with genetic resistance to HIV the 'Boston patients' also differ in several respects, which could provide important clues about how remission from active HIV infection could be achieved in other people with longstanding HIV infection.

The findings were reported by Timothy Henrich of Brigham and Womens Hospital, Boston, who has led the team conducting extensive tests on the patients. They concern a small group of people with HIV who were evaluated after hematopoietic stem cell transplants for lymphoma at hospitals in Boston (transfer of stem cells that will replace all blood cells, derived the from genetically matched donors). Three patients were originally evaluated but one died of recurrent Hodgkin's lymphoma six months after the transplant.

Both the surviving patients had been receiving prolonged antiretroviral therapy and received stem cell transplants with a reduced-intensity conditioning regimen of chemotherapy designed to eradicate the cancer and eliminate the existing bone marrow. In the case of the two patients under investigation, the conditioning regimen did not include radiotherapy and it did not eliminate the residual lymphocyte population. In contrast, the 'Berlin patient' received a much more aggressive regimen which eliminated existing bone marrow cells.

The transplants also differed from the 'Berlin patient' because they did not come from donors with genetic resistance to HIV infection (a CCR5 delta 32 mutation), so the cells were susceptible to HIV infection.

Measurements of HIV DNA showed that, around 200 days after transplant, HIV DNA levels had declined below 50 log copies per million PBMCs (peripheral blood mononuclear cells, part of the immune system) in one patient, while HIV DNA fell below this level around 280 days after transplant in the other patient. In both cases, HIV DNA levels have continued to decline after this point. After transplantation, the two patients have been followed for 21 (patient A) and 42 months (patient B), respectively.

More sensitive HIV DNA testing using larger samples of blood obtained by leukapheresis and rectal tissue biopsy showed that HIV DNA was below the limit of detection in both patients. Patient A provided a sample of 25 million PBMCs, and testing with a limit of detection of 0.07 copies per million PBMCs failed to detect HIV DNA. Patient B provided a sample of 50 million PBMCs, and testing with a limit of detection of 0.01 international units per million PBMCs similarly failed to detect HIV DNA.

Viral co-culture from CD4 lymphocytes failed to detect HIV in either patient. A rectal biopsy in patient B failed to detect HIV DNA in rectal cells that would be expected to provide a reservoir for HIV (limit of detection 2 copies per million cells).

After establishing that HIV DNA could not be detected, the researchers conducted extensive discussions with the patients and healthcare providers over a six-month period about the acceptability of an experimental treatment interruption in order to test viral control off medication.

Both patients consented after review of the study protocol by an internal review board. The patients are now being intensively monitored with weekly viral load (RNA) tests and bi-weekly testing of HIV DNA in PBMCs and, after six to eight weeks, the patients gave large volumes of blood for more sensitive analysis of HIV DNA. Leukapheresis will be repeated every three months.

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Two stem cell transplant recipients now controlling HIV off treatment

Stem Cell Transplants Clear HIV in Two Patients in Study

By Stem Cell Treatment

Two cancer patients in Boston who were also infected with HIV have no trace of the virus after receiving stem-cell transplants, suggesting they may have been cured of the AIDS-causing infection.

The two patients, treated at Brigham and Womens Hospital, stopped HIV treatment after the transplants, which in other patients has opened the door for the virus to come roaring back. In one patient there was no sign of the virus 15 weeks after stopping treatment, while the other has gone seven weeks without HIV rebounding, according to results presented today at the International AIDS Societys meeting in Kuala Lumpur.

The researchers led by Timothy Henrich of Harvard Medical School and Brigham and Womens Hospital said its too early to conclude the two men have been cured and the virus may be lingering in their brains or gut. Still, their cases are similar to that of Timothy Brown, the so-called Berlin patient, who was the first person to be cured of HIV after getting a bone marrow transplant for leukemia in 2007.

While stem-cell transplantation is not a viable option for people with HIV on a broad scale because of its costs and complexity, these new cases could lead us to new approaches to treating, and ultimately even eradicating, HIV, Kevin Robert Frost, the chief executive officer of amfAR, The Foundation for AIDS Research, which funded the study, said in a statement.

There was one main difference between Brown and the two Boston men: the cells he received contained a rare genetic mutation called CCR5 that made him resistant to HIV infection. The donors in the new cases lacked that mutation, and the Boston patients didnt undergo the intensive chemotherapy Brown did.

Scientists had believed the CCR5 mutation was key to Brown being cured. Theyll be searching through the new results for clues to whether other genes may hold promise against HIV, Rowena Johnston, amfARs director of research, said in an e-mail.

This stuff is really very exciting scientifically, and it really captures the imagination of the patients, said Paul E. Sax, a professor of medicine at Harvard Medical School and a clinician at Brigham and Womens. All of us get asked by our patients about these cases, even to the point of people actually requesting bone marrow transplants.

While AIDS drugs such as Gilead Sciences Inc. (GILD)s Atripla reduce HIV to undetectable levels in the body, making it a chronic disease, they dont completely clear it. The virus hides in certain immune cells, where it switches off the normal process of replication. That enables HIV to avoid detection by the medicines, which are designed to block steps in its reproduction.

Studies have shown that when patients who have the virus under control stop treatment, latent HIV reactivates and comes roaring back, forcing victims to resume daily pill therapy.

Doctors in March said they had cured an infant born with HIV for the first time by treating her with AIDS drugs about 30 hours after she was born at a rural Mississippi hospital. At 18 months the mother took the child off medication, and when the virus had not returned 10 months later, she was deemed functionally cured.

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Stem Cell Transplants Clear HIV in Two Patients in Study

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