UC Davis Health System researchers who are working to speed therapies to patients suffering from critical limb ischemia, osteoporosis and Huntington's disease received approval today for three separate research grants from the state's stem cell agency totaling more than $53 million. Each of the research studies that can now begin at UC Davis are specifically designed to lead to U.S. Food and Drug Administration approval of human clinical trials using stem cells and regenerative therapies.
At today's meeting of the California Institute for Regenerative Medicine (CIRM) in San Francisco, the agency's 29-member governing board approved five other grant proposals as part of its $150 million Disease Team Research Awards program. Funding goes to a highly select group of scientific collaborations to accelerate the state's most promising stem cell research.
"Today's Disease Team awards reflect the expertise and experience that UC Davis brings to the world of regenerative medicine," said Jan Nolta, professor of internal medicine and director of the UC Davis Stem Cell Program and its Institute for Regenerative Cures in Sacramento. "Our teams are as eager as patients and families themselves to begin the type of clinical research that will allow us to discover new therapies and cures for people suffering from chronic and life-debilitating diseases. These generous grants allow our researchers to focus as never before on finding the best answers to the most challenging questions in regenerative medicine."
The three UC Davis grants that were funded "are breathtaking in their size, scope and potential," said Nolta.
Critical limb ischemia (CLI)
Armed with their new $14.1 million CIRM grant, Nolta and John Laird, professor of cardiovascular medicine and director of the UC Davis Vascular Center, lead a team that plans to launch human clinical trials for critical limb ischemia, a vascular disease affecting about 2 million people around the country. The condition, which is often present in individuals with diabetes and severe peripheral artery disease, is caused by severe obstructions of the arteries, seriously decreasing blood flow to the feet and legs. It is associated with pain, debilitating foot ulcers, gangrene, and increased risk of leg amputation and death. Despite the best surgical revascularization efforts, at its end stages, this disease lacks effective therapies.
Bolstered by their recent preclinical studies in critical limb ischemia that showed stem cell safety and efficacy, Nolta and Laird plan to use mesenchymal stem cells from healthy bone marrow donors that are bioengineered to produce a revascularizing factor. The cells will be injected into the legs of CLI patients and are expected to migrate to oxygen-low areas in a patient's diseased limbs.
"Our combination stem cell strategy is analogous to a paramedic vehicle that can deliver emergency care directly to a patient," said Laird, who has been investigating different stem cell approaches as possible vascular therapies for several years. "We've seen that the special growth factors produced by our engineered stem cells can rapidly restore blood flow in the limbs of animal models that had no leg circulation whatsoever. Our CIRM grant now enables us to completely focus on finalizing safety and efficacy tests for humans so we can move this candidate therapy into clinical trials that will hopefully save people from amputation."
Joining the UC Davis team in developing the novel mesenchymal stem cell therapeutic for CLI will be research partners at Reina Sofia University Hospital in Cordoba, Spain. The collaboration is a part of the Andalusian Initiative for Advanced Therapies, which was created by the regional government of Andalusia to sponsor non-commercial clinical trials in the field of cellular therapy.
Treatment for osteoporosis
Nancy Lane, professor of internal medicine, will use her $20 million CIRM grant to lead her research team to optimize the use of a small molecule (LLP2A-Ale) to direct endogenous mesenchymal stem cells to the bone surface for the treatment of osteoporosis. The novel approach has the potential to promote new bone growth and provide an effective answer for men and postmenopausal women and who suffer from a disease that causes increased bone fragility and often leads to bone fractures and a significantly decreased quality of life.
Osteoporosis results from estrogen deficiencies and aging. It is the most common type of bone disease, and is expected to affect more than 61 million Americans by 2020. The disease occurs when the equilibrium between the formation of new bone and the reabsorption of old bone is disrupted in the body. In the U.S., 40 percent of women and 13 percent of men over the age of 50 will suffer an osteoporosis-related fracture in their lifetimes, with resulting pain and limitations on activity. Lane's proposal to CIRM noted that California has one of the nation's largest over-age-65 populations and can expect to experience greatly increased fracture rates because of the disease.
"The only currently approved therapy for osteoporosis that increases bone formation requires costly and inconvenient daily injections for two years," said Lane, who also serves as director of the UC Davis Musculoskeletal Diseases of Aging Research Group. "I'm very optimistic that with our Disease Team grant from CIRM, we will be able to successfully, and fairly quickly, develop a bone-building treatment of osteoporosis that only requires an occasional infusion."
In addition to research that will be done on UC Davis' Sacramento campus, Lane's CIRM grant represents economic-development opportunities for California businesses. It will contract with several companies to perform the crucial, preclinical studies that will ensure the small-molecule drug used to direct the bone-forming mesenchymal stem cells is safe. UC Davis will work with another company to synthesize and package the novel small-molecule compound for clinical trials. And yet another company will assist the university's disease team in working with FDA as the osteoporosis clinical trial gets under way, which is expected to occur in 2014. These collaborations are valued at approximately $3.5 million per year over the next four years.
Huntington's disease (HD)
The research that will lead to clinical trials for Huntington's disease (HD) represents one of the most exciting developments in regenerative medicine. Armed with a new CIRM grant, Vicki Wheelock, clinical professor of neurology and director of the HDSA Center of Excellence at UC Davis, will be working with Nolta on a $19 million push to launch the first FDA-approved cellular therapy for HD patients. Their plan is to infuse specially engineered mesenchymal stem cells into the brain tissue of Huntington's disease patients. The stem cells, which will be engineered to secrete brain-derived neurotrophic factor (BDNF), are designed to restore the health of brain cells damaged by the mutant Huntingtin (htt) protein that is the hallmark for the devastating neurodegenerative disease. This therapy has been shown to be effective in animal models of HD.
"About 1 in 10,000 Californians has Huntington's disease," said Wheelock. "It touches all races and socioeconomic levels. The financial burdens are in the billions, the emotional costs are immeasurable, and right now there is no cure. HD patients and family members have been tireless advocates for stem cell research. The CIRM grant enables us to work toward the first ever FDA-approved stem cell therapy for the disease. For physicians who have witnessed the tragedy of this illness over and over again, today we have hope for developing a disease-modifying treatment for HD and optimism for finding a cure."
Huntington's disease is an inherited disorder passed down through families in which brain cells waste away, or degenerate. While most patients develop symptoms as adults, children and teens can develop juvenile HD. Movement, judgment, thinking and speech decline, and psychiatric symptoms are very disabling. Over the course of the disease, patients suffer painful involuntary movements and loss of independence. Many people who are at risk are reluctant to be tested for fear they may lose health insurance or their jobs, and families of HD victims face the added challenges and costs of long-term caregiving.
The UC Davis trials for treating HD are targeted for earlier phases of the disease, when patients are younger and before the illness's full impact can take its toll. Wheelock said that mesenchymal stem cells represent remarkably effective delivery vehicles because they move well through tissue and can produce high levels of growth factor for uptake by the damaged neurons.
In preparation for a phase I clinical trial, the Huntington's disease team is carefully testing its proposed cellular infusion therapy for safety and effectiveness. In HD mouse models, the team has demonstrated that the delivery of brain-derived neurotrophic factors via mesenchymal stem cells significantly reduces behavioral deficits back to nearly normal levels.
"What's also exciting about our study is that our biological delivery system shows great promise for treating other neurodegenerative disorders such as amyotrophic lateral sclerosis (Lou Gehrig's disease), spinocerebellar ataxia, Alzheimer's disease, and even some forms of Parkinson's," said Wheelock. "Moreover, because HD patients have few other options, the benefit-to-risk ratio for our planned clinical trial is very high, and today's CIRM grant will enable us to move forward."
The state's latest round of stem cell grants to UC Davis represent the largest single-day amount ever earmarked for regenerative medicine research at the university, and nearly equals the total amount of funding it has received from CIRM over the past six years.
"We know that one of CIRM's primary goals with its awards is to enable teams of laboratory scientists, clinicians and junior investigators to tackle the most clinically relevant treatment issues and overcome potential safety problems as early in the research process as possible," said Frederick J. Meyers, executive associate dean for UC Davis School of Medicine, who oversees the school's research, teaching, clinical care and community engagement. "We are honored to receive the agency's support."
Meyers emphasized the role many people, including donors, have played in expanding the stem cell research program at UC Davis.
"Along with talented teams and state grants, our research success also is the result of visionary private donors who have been catalysts for funding our scientists and projects that will have far-reaching benefits for improving human health," he said.