Two teams of UCSF scientists have received grants from the California Institute for Regenerative Medicine to advance their stem cell based strategies for treating diabetes and brain tumors. The intent of the grants is for teams to file new drug applications to the U.S. Food and Drug Administration within four years, driving potential therapies toward clinical trials.
The two grants, awarded to collaborative scientific teams, total $39.2 million.
The diabetes grant is co-led by investigator Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center, in collaboration with Novocell, Inc. Other UCSF members of the team are Michael German, MD, PhD; Matthias Hebrok, PhD; and Qizhi Tang, PhD.
The brain tumor grant is led by Mitchel Berger, MD, chair of the UCSF Department of Neurosurgery, in collaboration with Ludwig Institute for Cancer Research and Burnham Institute for Medical Research. Other UCSF members of the team are C. David James, PhD; Tomoko Ozawa, MD, PhD; Russell Pieper, PhD; Mei-Yin Polley, PhD; Michael Prados, MD; and Elizabeth Read, MD.
The projects are among 14 disease team grants announced today (Oct. 28, 2009) by CIRM. The grants focus on conditions ranging from brain tumors and diabetes to HIV, heart damage and amyotrophic lateral sclerosis, among others. They are the first issued by CIRM with the explicit intent of driving the development of therapies for approval by FDA for testing in clinical trials.
The multidisciplinary collaborations are intended to hasten the clinical trial development process, avoiding mistakes sometimes discovered late in the game and ensuring that clinically relevant issues are considered early.
The diabetes team, lauded as a "dream team" by the CIRM working group reviewers, received $19,999,937 over four years. The goal is to encapsulate islet progenitor cells generated from human embryonic stem cells in a durable, retrievable device and implant them into patients. The cells, which differentiate into glucose responsive islet beta cells after transplantation in vivo, have proven to be a successful strategy in treating rodents with chemically-induced diabetes.
"The critical early proof-of-concept milestones have been completed," says Bluestone. "Now we need to perform the manufacturing and laboratory testing required to assure reliable production of a safe and effective product, thereby generating the data needed to seek Food and Drug Administration approval to test the therapy in humans."
"This is a very exciting early pre-clinical step, but, as is always the case in science, there are likely to be unexpected hurdles as we move forward," he says.
If successful, a Phase 1 safety trial in Type 1 diabetic patients could begin in three-four years from the initiation of the project.
The brain tumor team, which received $19,162,435, was characterized by the CIRM leaders as "pioneers and leaders in their respective fields." The team will refine their strategy of using adult and fetal neural stem cells, as well as mesenchymal stem cells, genetically engineered to contain a tumor-killing gene to home in on glioblastoma multiforme, the most common and aggressive form of brain tumor. The studies in rodents engineered to develop human brain tumors were successful.
The strategy is based on the team's discovery that neural stem cells naturally seek out brain tumor cells and other types of disease cells. "If successful, this approach would be an important advance in treating brain tumors of all kinds," says Berger. "Current approaches -- surgery, radiation, pharmacological drugs and gene therapies -- are unable to reach widely disseminated tumor cells that become dispersed within normal brain structures."
If the strategy is approved by the FDA, it would be tested first in patients with recurring glioblastoma multiforme.
Diabetes Disease Team grant
In Type 1 diabetes, the body's immune system turns against itself, destroying pancreatic beta cells. These cells produce insulin, a hormone that controls the amount of sugar in the blood stream. In Type 2 diabetes, caused by lifestyle factors such as obesity, the body's ability to respond to, or produce insulin is reduced. In both cases, without insulin, blood sugar can increase to toxic levels. While pharmaceutical insulin is commonly used to control diabetes, it does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes remain.
The diabetes disease team has developed a strategy in which they prompt human embryonic stem cells to differentiate into islet progenitor cells in the lab and then transplant the cells into rodents, where they differentiate into mature, insulin-producing beta cells.
To prevent the immune system's reaction to the cells -- either the auto-immune attack that would continue to occur in Type 1 diabetics or the normal immune system rejection to foreign cells that occurs in any transplant setting - the team has explored two strategies. One involves administering the cells inside a simple device, implantable under the skin. The other involves using next-generation pharmaceuticals, some of which have been approved recently by the FDA, that enable transplantation between unmatched individuals without major side effects.
The work will include identifying the best means for introducing cells into patients.
Brain Tumor Disease Team grant
The brain tumor disease team will derive human adult and fetal neural stem cells and mesenchymal stem cell lines, each cell line having been proffered as therapeutic, but never having been compared head-to-head in treating tumors. Each cell line will be modified using two therapeutic genes. One of the genes expresses a protein known as TRAIL that specifically kills tumor cells, but does not harm normal cells and tissues. The other expresses cytosine deaminas, an enzyme that converts a non-toxic chemical into a toxic chemotherapeutic.
The goal is to identify the most effective neural stem cell and therapeutic gene combination to advance for clinical trial in patients with brain tumors.
"These studies are a vital opportunity to explore the behavior of stem cells in patients," says Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
Global gap in diabetes prevalence and treatment has widened since 1990