Diagnosis
Sanford-Burnham Medical Research Institute in La Jolla, was representing the new-new thing: the notion that someday stem cells would play a role in gene therapy.
Even for Snyder, the idea of genetically engineering these newly discovered cells was purely theoretical. His work avoided the crowded field of genetics—a field awash in senior investigators. He stuck with the less-populated stem cell specialty, counting on the big fish/small pond equation to help his career.
Then his best friend was diagnosed with a deadly brain tumor. The children of Dr. James A. Galambos approached Snyder. Was there anything he could do? The question altered his course and he began a collaboration that included a new graduate student dedicated to using stem cells to tackle glioma.
In 2000, a paper in the Proceedings of the National Academy of Science bore a dedication to Snyder’s late friend. It announced a finding that holds so much promise for the treatment of brain tumors that two grants from the California Institute for Regenerative Medicine are based on it, together totaling $37 million. Neural stem cells, it revealed, are attracted to tumors like moths to a light. If they could be made to carry a chemotherapeutic payload, they could serve as weapons against the wanton spread of metastatic brain cancer.
Snyder, senior author on that PNAS paper, is a co-investigator on one CIRM grant that intends to exploit this feature of stem cell behavior. Karen Aboody, the PNAS paper’s first author, is the principal investigator on the other grant that will use neural stem cell’s strange attraction to her advantage. Aboody, M.D., was the graduate student Snyder had added to his lab. Today she is an associate professor at City of Hope in Duarte.
Studies in mice using this stem-cell-based weapon against brain tumor have been remarkably successful. “When we tried it, 90 percent of the animals survived,” Aboody said. Without the stem cell targeting, only 30 percent lived.
This attack on brain cancer is just one example of a new breed of therapy based on stem cells manipulated to become useful therapies. What Snyder presented as theory to that roomful of distracted conference attendees is now a field that’s being mined for new treatments for glioma, HIV/AIDS, sickle cell anemia, heart disease and a rare skin disorder called epidermolysis bullosa, all of which are the focus of CIRM disease team awards. These teams are expected to bring their manipulated stem cells to the FDA to begin clinical trials within four years.
Genetic Resistance
Since the discovery of HIV/AIDS, researchers have puzzled over a handful of people who never contracted the virus despite repeated exposure. By the early 1990s scientists had identified a rare mutation as the protective agent.
“A person living with HIV, even with well controlled virus, even with antiretroviral treatment is looking at least a 10-year shorter life expectancy.”
- Jeff Sheehy
To enter immune cells, HIV docks with two proteins on the cell’s surface — a primary receptor known as CD4, and a secondary receptor called CCR5. HIV-resistant patients make an altered CCR5 protein that prevents the virus from docking. A team of German researchers put this knowledge to work and in 2009 published a paper in the New England Journal of Medicine describing a stem cell transplant given to a 40-year-old leukemia patient infected with HIV. The Berlin researchers used a matching donor who carried the mutated CCR5 genes. Today, the recipient of those cells, known as the Berlin patient, is considered functionally cured of HIV. He takes no HIV medication, has no disease symptoms, and shows no apparent virus in his body.
This news of the German stem cell transplant fuels hope for these new stem-cell approaches, says Jeff Sheehy, communications director at the AIDS Research Institute at the University of California, San Francisco and CIRM governing board member.
“Until Berlin, there wasn’t much promise for HIV and stem cells,” Sheehy said.
The new stem-cell therapeutic approach comes at what has been a sobering moment in the history of AIDS treatment, Sheehy said.
Despite years of effort, there is still no vaccine against the disease on the horizon, and successful antiretroviral therapy, while saving many lives, is generally unavailable in the developing world, and remains enormously expensive. It comes with a growing list of side effects, including a rise in heart disease, an increase in non-HIV related cancers, such as lung cancer, and elevated cholesterol and triglyceride levels. “
"A person living with HIV, even with well-controlled virus, even with antiretroviral treatment, is looking at least a 10 year shorter life expectancy,” Sheehy said.
Despite the hope embodied by the Berlin patient, transplantation isn’t considered a widespread cure for HIV/AIDS according to John Zaia, M.D., chair of virology at City of Hope, who leads one of the two HIV/AIDS disease teams. Zaia’s team, and a second team lead by Irvin Chen, Ph.D., director of the AIDS Institute at UCLA, plan instead to genetically interfere with CCR5 in the blood-forming stem cells of HIV patients.
Although the details of the research plans differ, they are similar in their general outline: harvest a patient’s blood-forming cstem ells, genetically alter the cells outside the body so they no longer produce the CCR5 protein, and return the HIV-resistant cells to the patient where they will reform the patient’s entire blood system.
A related disease team project, led by Donald Kohn, M.D. at UCLA, will also modify blood-forming stem cells, this time to treat people with sickle cell anemia. The disease is caused by a mutation in a gene that makes the oxygen-carrying protein in blood. After modifying those cells to make a normal version of the protein, called hemoglobin, they’ll give the cells back to the patient and reform the blood system with normal, healthy blood.
Manipulating the Numbers
There’s more than one way to modify a stem cell. Although the HIV/AIDS and sickle cell teams rely on genetic modifications, a team lead by Eduardo Marban at Cedars-Sinai in Los Angeles is manipulating the numbers. His team plans to attack heart failure by harvesting tidbits of heart muscle and multiplying the regenerative cells within to much higher numbers than naturally occur in the heart. In four weeks, some 25 million stem cells will be available to inject directly into the muscle of a failing heart using special needle injection catheters. With the successful completion of animal trials, Marban hopes to start studies in patients with severe heart failure in about two years.
"Even though we've gotten better at treating heart failure, when patients are sufficiently afflicted -- they have shortness of breath and decreased ability to exercise -- the mortality for this disorder exceeds that of many malignant tumors," he said.
Although heart transplantation can save lives, there are only 2,000 donor hearts available every year, and nearly 100,000 people a year who need them.
"Stem cell-based treatment could be a cellular transplantation alternative to organ transplant," Marban said.
Even for Snyder, the idea of genetically engineering these newly discovered cells was purely theoretical. His work avoided the crowded field of genetics—a field awash in senior investigators. He stuck with the less-populated stem cell specialty, counting on the big fish/small pond equation to help his career.
Then his best friend was diagnosed with a deadly brain tumor. The children of Dr. James A. Galambos approached Snyder. Was there anything he could do? The question altered his course and he began a collaboration that included a new graduate student dedicated to using stem cells to tackle glioma.
In 2000, a paper in the Proceedings of the National Academy of Science bore a dedication to Snyder’s late friend. It announced a finding that holds so much promise for the treatment of brain tumors that two grants from the California Institute for Regenerative Medicine are based on it, together totaling $37 million. Neural stem cells, it revealed, are attracted to tumors like moths to a light. If they could be made to carry a chemotherapeutic payload, they could serve as weapons against the wanton spread of metastatic brain cancer.
Snyder, senior author on that PNAS paper, is a co-investigator on one CIRM grant that intends to exploit this feature of stem cell behavior. Karen Aboody, the PNAS paper’s first author, is the principal investigator on the other grant that will use neural stem cell’s strange attraction to her advantage. Aboody, M.D., was the graduate student Snyder had added to his lab. Today she is an associate professor at City of Hope in Duarte.
Studies in mice using this stem-cell-based weapon against brain tumor have been remarkably successful. “When we tried it, 90 percent of the animals survived,” Aboody said. Without the stem cell targeting, only 30 percent lived.
This attack on brain cancer is just one example of a new breed of therapy based on stem cells manipulated to become useful therapies. What Snyder presented as theory to that roomful of distracted conference attendees is now a field that’s being mined for new treatments for glioma, HIV/AIDS, sickle cell anemia, heart disease and a rare skin disorder called epidermolysis bullosa, all of which are the focus of CIRM disease team awards. These teams are expected to bring their manipulated stem cells to the FDA to begin clinical trials within four years.
Genetic Resistance
Since the discovery of HIV/AIDS, researchers have puzzled over a handful of people who never contracted the virus despite repeated exposure. By the early 1990s scientists had identified a rare mutation as the protective agent.
“A person living with HIV, even with well controlled virus, even with antiretroviral treatment is looking at least a 10-year shorter life expectancy.”
- Jeff Sheehy
To enter immune cells, HIV docks with two proteins on the cell’s surface — a primary receptor known as CD4, and a secondary receptor called CCR5. HIV-resistant patients make an altered CCR5 protein that prevents the virus from docking. A team of German researchers put this knowledge to work and in 2009 published a paper in the New England Journal of Medicine describing a stem cell transplant given to a 40-year-old leukemia patient infected with HIV. The Berlin researchers used a matching donor who carried the mutated CCR5 genes. Today, the recipient of those cells, known as the Berlin patient, is considered functionally cured of HIV. He takes no HIV medication, has no disease symptoms, and shows no apparent virus in his body.
This news of the German stem cell transplant fuels hope for these new stem-cell approaches, says Jeff Sheehy, communications director at the AIDS Research Institute at the University of California, San Francisco and CIRM governing board member.
“Until Berlin, there wasn’t much promise for HIV and stem cells,” Sheehy said.
The new stem-cell therapeutic approach comes at what has been a sobering moment in the history of AIDS treatment, Sheehy said.
Despite years of effort, there is still no vaccine against the disease on the horizon, and successful antiretroviral therapy, while saving many lives, is generally unavailable in the developing world, and remains enormously expensive. It comes with a growing list of side effects, including a rise in heart disease, an increase in non-HIV related cancers, such as lung cancer, and elevated cholesterol and triglyceride levels. “
"A person living with HIV, even with well-controlled virus, even with antiretroviral treatment, is looking at least a 10 year shorter life expectancy,” Sheehy said.
Despite the hope embodied by the Berlin patient, transplantation isn’t considered a widespread cure for HIV/AIDS according to John Zaia, M.D., chair of virology at City of Hope, who leads one of the two HIV/AIDS disease teams. Zaia’s team, and a second team lead by Irvin Chen, Ph.D., director of the AIDS Institute at UCLA, plan instead to genetically interfere with CCR5 in the blood-forming stem cells of HIV patients.
Although the details of the research plans differ, they are similar in their general outline: harvest a patient’s blood-forming cstem ells, genetically alter the cells outside the body so they no longer produce the CCR5 protein, and return the HIV-resistant cells to the patient where they will reform the patient’s entire blood system.
A related disease team project, led by Donald Kohn, M.D. at UCLA, will also modify blood-forming stem cells, this time to treat people with sickle cell anemia. The disease is caused by a mutation in a gene that makes the oxygen-carrying protein in blood. After modifying those cells to make a normal version of the protein, called hemoglobin, they’ll give the cells back to the patient and reform the blood system with normal, healthy blood.
Manipulating the Numbers
There’s more than one way to modify a stem cell. Although the HIV/AIDS and sickle cell teams rely on genetic modifications, a team lead by Eduardo Marban at Cedars-Sinai in Los Angeles is manipulating the numbers. His team plans to attack heart failure by harvesting tidbits of heart muscle and multiplying the regenerative cells within to much higher numbers than naturally occur in the heart. In four weeks, some 25 million stem cells will be available to inject directly into the muscle of a failing heart using special needle injection catheters. With the successful completion of animal trials, Marban hopes to start studies in patients with severe heart failure in about two years.
"Even though we've gotten better at treating heart failure, when patients are sufficiently afflicted -- they have shortness of breath and decreased ability to exercise -- the mortality for this disorder exceeds that of many malignant tumors," he said.
Although heart transplantation can save lives, there are only 2,000 donor hearts available every year, and nearly 100,000 people a year who need them.
"Stem cell-based treatment could be a cellular transplantation alternative to organ transplant," Marban said.