A team of Cedars-Sinai Heart Institute heart attack patients.

The grant will be used to continue Marbán’s development of cardiac stem cell therapies to strengthen and heal damaged heart muscle caused by cardiac arrest. The grant is part of a new strategy by the California state stem cell agency aimed at speeding the process of moving medical research from the laboratory to patient care.

Generally, it can take a decade or more to develop a new medical treatment to the point of securing federal approval for a clinical trial. The state institute’s Disease Team Research Awards, however, are designed to help researchers develop medical theories into treatments tested by clinical trials in four years or less.

Marbán’s team was one of 11 in California to receive a Disease Team Research Award and is the only team focusing on heart disease. Heart disease is the leading cause of death in the United States. According to the Centers for Disease Control, in 2009, an estimated 785,000 Americans will have a first-time heart attack and about 470,000 will have a recurrent attack.

Earlier this year, Marbán, who is director of the Cedars-Sinai Heart Institute, and his team completed the first procedure in which a patient’s own heart tissue was used to grow specialized heart stem cells that were then injected back into the patient’s heart in an effort to repair and re-grow healthy muscle in a heart that had been injured by a heart attack. The minimally-invasive procedure was completed on the first patient on June 26.

The Disease Team Award will enable Marbán’s team to develop other, new stem cell therapies for heart patients, including a potential treatment for patients with advanced heart failure.

“The support Cedars-Sinai is receiving from the California Institute for Regenerative Medicine will be an important element to succeeding in the fight against heart disease,” Marbán said. “What we work on in our stem cell lab today could translate into tomorrow’s innovative treatment for heart attack patients.”

“We are delighted that Dr. Marbán is receiving CIRM funding to continue his groundbreaking translational science devoted to regenerating diseased myocardial tissue,” said Shlomo Melmed, M.D., Cedars-Sinai Medical Center vice president of academic affairs and dean of the medical faculty. “This award validates the leading role of the Cedars-Sinai Heart Institute in developing cutting-edge treatments for heart disease.”

Source: Sally Stewart

Cedars-Sinai Medical Center

Two teams of UCSF scientists have received grants from the California Institute for Regenerative Medicine to advance their 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 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 working group reviewers 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.

More on the grant: http://www.cirm.ca.gov/ReviewReports_DR1-01423

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 deaminase, 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.

Source: Jennifer O’Brien

University of California - San Francisco

The National Institutes of Health is launching a large multicenter randomized clinical trial to determine whether maintaining blood pressure levels lower than current recommendations further reduces the risk of cardiovascular and kidney diseases, or age-related cognitive decline.

Called the Systolic Blood Pressure Intervention Trial (SPRINT), the nine-year, $114 million study will be conducted in more than 80 clinical sites across the United States.

Current clinical guidelines recommend systolic pressure (the top number in a blood pressure reading) of less than 140 millimeters of mercury (mm Hg) for healthy adults, and 130 mm Hg for adults with kidney disease or diabetes. SPRINT will evaluate the potential benefits of maintaining systolic blood pressure at less than 120 mm Hg for adults who are at risk for heart disease or kidney disease. The study will also assess possible risks of this therapeutic strategy.

Study participants will be treated with commonly available blood pressure medications to achieve one of two different levels of blood pressure control - either less than 140 mm Hg (standard group) or less than 120 mm Hg (treatment group). Those in the treatment group will take an average of three to four medications; those in the standard group will take about two medications. SPRINT participants will be seen in clinics every few months at the beginning of the study and less frequently as their blood pressure is controlled. The study will include standard tests for determining the health of the heart, kidneys, and brain.

The clinical trial is based in large part on observational studies that suggest that maintaining a lower blood pressure level than is currently recommended reduces the risk of cardiovascular diseases.

High blood pressure is one of the most common conditions among middle-aged and older adults, and is a leading risk factor for stroke, heart disease, kidney failure, and other conditions. High blood pressure is also a key contributor to the development and progression of chronic kidney disease. SPRINT will examine the hypothesis that more aggressive blood pressure control will slow the development of chronic kidney disease beyond the benefit achieved by current blood pressure goals. Nearly 1 in 3 adult Americans has high blood pressure. Worldwide estimates suggest that over 900 million adults have high blood pressure.

“SPRINT is an important comparative effectiveness research study for a common and potentially costly condition. The combined expertise and resources of four institutes of the NIH maximizes our efforts to develop the scientific evidence to help patients and their doctors determine the best treatment options for them,” stated NIH Director Francis S. Collins, M.D., Ph.D.

Blood pressure numbers are written with the systolic number above or before the diastolic number, such as 120/80 mmHg. Systolic pressure is the pressure on the arteries when the heart beats and pumps blood through the arteries, and diastolic pressure is the pressure when the heart is filling with blood between beats. Although systolic and diastolic measures are important, research has found that systolic pressure is a strong predictor of vascular problems caused by high blood pressure, especially among older individuals.

“To determine if a lower blood pressure goal reduces the risk of complications and death more than standard treatment to the current recommended goal level, we need evidence-based research. Only a large, long-term clinical trial comparing the two levels will give us the answer,” said Elizabeth G. Nabel, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI). “If this study shows that maintaining a lower systolic blood pressure has significant benefits for middle-aged and older adults - and doctors and patients meet the lower goal levels - we could see hundreds of thousands fewer heart attacks and stroke each year in the United States alone.”

“On the other hand, if the results suggest no benefit from the lower goal level, then we will know that patients need not pursue more aggressive treatment than is currently recommended, which could save money and lower their risk of possible side effects from more intense treatment,” added Nabel.

SPRINT is funded by the NHLBI and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Two other NIH institutes - the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Aging (NIA) - will support SPRINT-MIND, a substudy that focuses on the impact of lowering systolic blood pressure to reduce cognitive impairment, an important early indication of dementia.

“Several observational studies suggest that elevated blood pressure could be an important factor leading to cognitive decline and dementia in older age,” said NIA Director Richard J. Hodes, M.D. “SPRINT-MIND will provide important evidence of whether managing systolic blood pressure at lower levels can slow cognitive decline - an important consideration in light of the aging population.”

Walter J. Koroshetz, M.D., NINDS deputy director, added, “It is critically important to know whether elderly persons with hypertensive cerebrovascular changes can tolerate such aggressive blood pressure lowering.”

SPRINT will enroll approximately 7,500 participants age 55 years or older with systolic blood pressure of 130 mm Hg or higher. Participants will have a history of cardiovascular disease; be at high risk for heart disease by having at least one additional risk factor, such as smoking or high blood cholesterol levels; or have chronic kidney disease. Patients with a history of stroke or diabetes are not expected to be studied in SPRINT because other randomized clinical trials, such as the NINDS Stroke Prevention in Small Subcortical Stroke (known as SPS3) study and the NHLBI Action to Control Cardiovascular Risk in Diabetes (known as ACCORD) trial, are currently testing similar strategies in these patients. These studies will help inform how SPRINT is designed and conducted.

Enrollment for SPRINT is expected to begin in fall 2010. Participants will be randomly assigned to one of two groups: to treat systolic blood pressure to the lower goal of less than 120 mm Hg or to treat to the standard goal of less than 140 mm Hg. Participants will be followed for at least four years. Researchers will then compare the two groups to see if the participants in the lower blood pressure group had fewer heart attacks or strokes; were less likely to develop heart failure or chronic kidney disease; or had less decline in cognitive function. Deaths due to cardiovascular disease and quality-of-life measures will also be studied. In addition, a subgroup of participants will have moderate, or stage 3, kidney disease at enrollment; they will be studied to determine the impact of lower blood pressure on their risk of cardiovascular disease as well as end-stage kidney disease.

SPRINT tests the effectiveness of a medical strategy to reach specific blood pressure goals and does not compare specific drugs to each other. Study participants will be given specific blood-pressure lowering medications as determined by their research clinicians; medications may differ among participants in each treatment group.

“SPRINT will be a landmark study as it will be the first large randomized clinical trial to study how maintaining systolic blood pressure at a level lower than currently recommended will impact cardiovascular and kidney diseases, and cognitive decline in adults without diabetes or history of stroke,” noted Lawrence J. Fine, M.D., Dr.P.H., chief of the Branch of Clinical Applications and Prevention and the SPRINT project officer at the NHLBI.

The clinical trial builds upon large, population-based studies that suggest that maintaining systolic blood pressure below 120 mm Hg may substantially lower the risk of cardiovascular diseases. Other observational studies suggest that high blood pressure is a risk factor for chronic kidney disease and dementia. In January 2007, a special ad hoc panel of scientific leaders in clinical high blood pressure research and clinical trials in cardiovascular disease convened by the NHLBI confirmed earlier recommendations that a clinical trial such as SPRINT is a top priority for cardiovascular research. According to a recent Cochrane review of scientific literature, no completed clinical trials have adequately tested the effects of the low systolic blood pressure target.

“Based on the results of other studies, the time is right for SPRINT,” added Fine.

The study coordinating center is Wake Forest University in Winston-Salem, North Carolina (Principal investigator: David Reboussin, Ph.D).

The SPRINT study clinical center networks are:

• Case Western Reserve University School of Medicine, Cleveland, Ohio (Principal investigator: Jackson T. Wright, M.D., Ph.D.)

• Department of Veterans Affairs, VA Medical Center, Memphis, Tennessee (Principal investigator: William C. Cushman, M.D.)
• University of Alabama, Birmingham (Principal investigator: Suzanne Oparil, M.D.)
• University of Utah, Salt Lake City, Utah (Principal investigator: Alfred K. Cheung, M.D.)
• Wake Forest University, Winston-Salem, North Carolina (Principal investigator: David C. Goff, Jr., M.D., Ph.D.)

Source: NHLBI Office of Communications

NIH/National Heart, Lung and Blood Institute