Stanford researchers receive $40 million to study potential stem cell therapies for heart failure and immune disorder

Robert Robbins, MD, believes that pluripotent stem cells are likely to be the ultimate cure for a broken heart. Now he and his colleagues at the Stanford University School of Medicine have the financial means to investigate whether this idea is true — in the form of a $20 million, four-year grant from the California Institute for Regenerative Medicine.

"This will be the first time anyone has implanted cells derived from human embryonic stem cells into a human heart," said Robbins, professor and chair of cardiothoracic surgery and director of Stanford's Cardiovascular Institute. "We're excited to assess this potential treatment for patients who currently have very few options other than heart transplant."

Joseph Wu is a co-investigator for a new grant that will enable Stanford researchers to test whether human embryonic stem cells can help heal damaged or poorly functioning hearts. Length: 1:46 minutes.

Robbins and his colleagues hope to move into human clinical trials within four years, after first testing the transplantation approach extensively in animal models. They plan to enroll about 10 patients in the proposed phase-1 trial.

Robbins wasn't the only Stanford investigator to be awarded funds from the state stem cell agency today. Associate professor of medicine Judith Shizuru, MD, PhD, also received $20 million to develop an antibody-based therapy to remove diseased blood stem cells in children with a condition called severe combined immunodeficiency, commonly known as "bubble boy disease." The research builds on discoveries in mice by Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine and a consultant to the Shizuru team. The researchers will investigate whether the antibody treatment enables patients to more readily accept a transplant of healthy donor cells. Weissman is also Stanford's Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research.

The $40 million awarded to Stanford is part of a total of $150 million awarded by the governing board of the state stem cell agency in this round of funding. The disease-team research grants are meant to quickly bring promising therapies to patients through teams that include basic scientists, clinicians and industry. Stanford investigators received $57.1 million during the first disease-team award round in October 2009.

"Everything we do in this innovative Disease Team Program is focused on getting good science converted to productive treatments for patients," said CIRM president Alan Trounson, PhD. "These awards reflect and highlight our commitment to identifying the most promising stem cell research and supporting it for the time needed to show both the safety and effectiveness of therapy, with an ultimate goal of producing a new treatment that is approved by the FDA for clinical application."

The stem cell agency's grants working group had originally recommended that six of the 21 applications for this round be funded. After deliberating, the board voted to fund an additional two grants and send five others back for additional review.

The grant awarded to Robbins and his collaborators will support the derivation of heart muscle cells called cardiomyocytes from a federally approved human embryonic stem cell line. The researchers will investigate whether the newly formed cardiomyocytes can heal poorly functioning or damaged hearts — first in animals, and then in a limited number of human patients with end-stage heart failure. About 4.8 million Americans suffer from congestive heart failure caused by heart attacks or other causes.

"This is really a multidisciplinary, multi-institute grant," said Stanford cardiologist and grant co-investigator Joseph Wu, MD, PhD. "We are collaborating with researchers from Gladstone, UCSF, UCLA, UCSD and the City of Hope. If our project is successful, we will then recruit patients who have been placed on a left ventricular assist device while they await a heart transplant. This will allow us to inject the cells at the time we implant the LVAD, and to assess their engraftment and cell fate when the patient's native heart is removed at the time of subsequent heart transplant."

Although the trial will be designed solely to test the safety of the cells, the physicians will also be alert for any signs of improved cardiac function in the period prior to transplant, said Robbins.

The Shizuru grant focuses on the use of a monoclonal antibody previously tested in mice by Weissman's group to remove, or deplete, diseased or dysfunctional blood and immune system stem cells in patients with severe combined immunodeficiency. Currently these cells must be killed by high-dose chemotherapy or radiation, a process that itself can be life-threatening, prior to transplantation with healthy donor cells. Shizuru and her collaborators plan instead to use an antibody that will specifically recognize and eliminate the faulty cells without the use of toxic treatments, enabling patients to more readily accept cells from a healthy donor.

In a public summary of their application, Shizuru and her colleagues noted that children with severe combined immunodeficiency are born without a functional immune system "and are therefore extraordinarily susceptible to serious infections. If children with SCID are not treated, most die by the age of 2. Bone marrow transplantation is the only established cure for this disease. Unfortunately, the likelihood of successful cure is reduced by the way transplants are currently performed, using toxic treatments to prepare the children to accept the donor cells." Experiments in mice have shown that the antibody, called CD117, allows the animals to more readily accept the subsequent transplant.

Although SCID is a relatively rare disorder, if proven effective this technique could be useful for other diseases, including sickle-cell anemia, diabetes, multiple sclerosis and cancers of the blood cells such as leukemias and lymphomas.

In addition to the Stanford grants, other diseases targeted by successful applicants for this round of CIRM funding include Huntington's disease, osteoporosis and spinal cord injury. The four-year grants are meant to safely and efficiently move ongoing stem cell research into clinically applicable therapies.

"Research on human embryonic stem cells and induced pluripotent cells has reached a critical point," said Wu. "There are not many options we can offer to patients with end-stage heart failure. We are very excited to offer the prospect of testing these cells in patients who desperately need new therapies in the future."

"We want to know if pluripotent stem cells are going to be able to replace damaged heart muscle," added Robbins. "This is a culmination of about 15 years worth of work with collaborators across Stanford. We're very enthusiastic about getting this opportunity to try to develop a treatment for people with damaged hearts."

CIRM was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for stem cell research at California universities and research institutions and required setting up the agency, CIRM, to oversee allocation of the money.


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