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Curing rather than treating hearts?

By Dawn Yankeelov

UofL teams led by Dr. Roberto Bolli are involved in multiple clinical trials investigating the use of stem cells to repair heart disease damage.

University of Louisville researcher Dr. Roberto Bolli’s findings about how a patient’s heart stem cells can be turned into a treatment that regenerates dead heart muscle continue to gain favorable recognition around the world.

This past July, Bolli travelled to Bordeaux, France, where the International Society for Heart Research bestowed on him its Peter Harris Distinguished Scientist Award, which recognizes a senior investigator for lifetime contributions of major discoveries in cardiovascular science. At home meanwhile, increased federal funding and new clinical trials will allow him to continue to build upon his promising research.

His work in cardiac regenerative medicine regarding stem cells and the heart, and related clinical studies, is one of the hottest areas of regenerative science research. Cardiovascular disease remains the leading cause of death worldwide, and one of the greatest needs is treatment methods for severe cardiac failure where traditional treatment or surgery is not an answer.

Dr. Bolli has been at the University of Louisville for 21 years, since December 1994, and serves as chief of UofL’s Division of Cardiovascular Medicine, director of the Institute of Molecular Cardiology and scientific director of the Cardiovascular Innovation Institute. He is vice chair for research in the Department of Medicine.

At his University of Louisville office you will find cherished framed copies of Circulation Research, a peer-review journal for which he is editor-in-chief. An American Heart Association committee selected Bolli in 2009 for a 10-year term overseeing the professional journal.

“We hope to contribute to moving the needle in cardiac treatment with stem cells here at UofL,” Bolli said. “These studies are totally new and we look to revolutionize medicine through this research.”

This regenerative therapy approach is qualitatively different than other treatments, he said, because “we are curing the disease, and removing the cause of heart failure. This is not a drug therapy approach.”

Bolli and groups he is leading at UofL are involved in several significant research projects.

The PACE Trial – UofL is part of an advanced research trial using new adult stem-cell therapy for patients with peri-pheral arterial disease in their legs and who face eventual amputation. The Phase I and Phase II trial is conducted under a National Institutes of Health grant as a member of the elite Cardiovascular Cell Therapy Research Network.

Only seven of 40 institutions that sought to be members of the Cardiovascular Cell Therapy Research Network were selected. In addition to UofL’s Bolli-led team, the others are: Stanford University; Texas Heart Institute; University of Florida; University of Miami; Minneapolis Heart Institute Foundation; and Indiana University.

UofL is one of the top two enrolling centers for the study, which Dr. Bolli said will continue accepting participant patients age 40 and over for a few more months.

Because conventional surgery is not an option, patients in this study are expected to eventually lose the use of their legs as the disease progresses and require amputation, Bolli explained.

Research under the seven-year grant was initiated after NIH awarded it in 2012. No preliminary research data is available yet.

Fixed and covered costs are approximately $3.5 million and each patient enrolled in the clinical research means additional dollars for the patient care. Protocols have been developed for approximately $10M in total and used in these studies primarily at Kentucky One’s Jewish Hospital Heart & Lung Institute.

The clinical trial is known as PACE and is a randomized, placebo-controlled study in which patients are followed for one-year. Patients with intermittent claudication – leg muscle pain, numbness, cramping or heaviness caused by obstructed arteries – will be injected with aldehyde dehydrogenase bright (ALDHbr) cells harvested from their bone marrow.

Intermittent claudication is a symptom 1 to 3 million Americans with peripheral arterial disease experience.

Manufacture of Stem Cells – UofL’s Cardiovascular Innovation Institute hopes to “manufacture” stem cells to combat peripheral arterial disease in a project Bolli will oversee. The principal investigators are at Indiana University in Indianapolis with UofL’s site slated to conduct the cell reproduction needed for this new research.

RENEW trial – UofL’s Institute for Molecular Cardiology is the only Kentucky site among the 50 U.S. sites participating in a nationwide Phase III clinical trial known as RENEW. It uses stem cells harvest from patients to see if they can lessen the debilitating effects of angina.

Originally planned for up to 2,000 patients, Baxter Pharmaceuticals decided to close clinical trial participation in early 2014. The several hundred patients already treated are being studied, according to Bolli.

2016: CONCERT-HF Trial – Another Bolli clinical trial expected to open for recruitment in early 2016 will look to validate the ability of replacing heart scar tissue with new muscle using stem cells. The new study will build on work Bolli completed several years ago.

In the previous SCIPIO trial, patients suffering heart failure due to a previous heart attack showed an average 12 percent improvement one year after being infused with their own stem cells, which tripled the anticipated improvement.

This new clinical work may require endomyocardial and bone marrow biopsies, cell cultures of both samples, and intramyocardial delivery of the cells. This is a randomized, placebo-controlled clinical trial for patients aged 21 to 79 who have a diagnosis of chronic ischemic left ventricular dysfunction secondary to myocardial infarction.

2016: SENECA Trial – This project investigates the value of giving stem-cell injections to cancer survivors who had taken medications for their cancer treatment that contributed to later heart failure. This Bolli trial will employ a one-year “treat and follow” approach and is seen as promising research, as there are no other real options for these patients.

(Detailed information on clinical trials is available at clinicaltrials.gov.)

The use of adult stem cells in clinical research has become more accepted, and Bolli said he expects to see nationwide studies of a larger scale in Phase III research using larger data sets within two to three years. For example, TEVA Pharmeuticals is sponsoring several trials in cardiology circles, and participating in this step to widespread commercialization.

The use of living organisms for treatment with cell therapy promises to see a surge in patents as well.

Meanwhile, Bolli has already applied for his first patent of a stem-cell type, separate from the trial cells.