Developing the Cell-Based Therapies of the Future
Article Summary
- Researchers at the Interdisciplinary Stem Cell Institute are investigating stem and other cell-based therapeutics to treat many of the conditions that beset the human body.
- ISCI Director Dr. Joshua Hare and his research team are running six clinical trials testing mesenchymal stem cells against diabetes, stroke, Alzheimer’s disease and cardiac disorders.
- Dr. Hare predicts that, within the next five to 10 years, doctors in the United States will be able to prescribe stem-cell based therapies for numerous conditions.
Researchers have long sought to harness stem cells and other cell-based approaches to regenerate tissue damaged by disease, injury and even aging. Through groundbreaking research, the Interdisciplinary Stem Cell Institute (ISCI), part of the University of Miami Miller School of Medicine, is realizing the promise of stem and other cell-based therapeutics to treat many, if not most, of the conditions that beset the human body.
Faculty at ISCI and their collaborators at the Miller School are investigating experimental therapies for targets throughout the body, through every stage of development, from basic science to clinical trials.
Tapping into such wide-ranging therapeutic potential means working across disciplines, according to Joshua Hare, M.D., ISCI’s founding director and the Louis Lemberg Professor of Medicine at the Miller School.
“At ISCI we’ve put together a team that has the capability to go into any domain of this field of regenerative medicine,” said Dr. Hare, also the Miller School’s senior associate dean for experimental and cellular therapeutics.
Following Through on Enthusiasm
The Miller School recruited Dr. Hare to found ISCI in 2007, a year after Japanese researchers succeeded in reprogramming adult stem cells to become pluripotent, or able to produce all the body’s cell types. This accomplishment would later earn the Nobel Prize. Around this time, Dr. Hare, a cardiologist, was attempting to coax mesenchymal stem cells, which differentiate into tissues that include muscle, to grow specialized cardiac muscle cells within organs damaged by heart attacks.
“There was huge enthusiasm 20 years ago that cell-based, regenerative medicine was a new approach to treating all diseases,” he said. “But it required a lot of basic research. Cell therapy for heart attack victims could fill an enormous, unmet medical need.”
It turned out that, when introduced into the heart, the mesenchymal stem cells did not themselves turn into new cardiac muscle. However, Dr. Hare’s research, which he has continued at ISCI, suggested that they did benefit the damaged heart by reducing injury from the heart attack and stimulating the heart to heal on its own.
Just as striking were the effects on patients’ overall health. A University of Miami-based clinical trial described in JAMA in 2012, for example, found that, after infusions of their own mesenchymal stem cells, heart failure patients felt better and increased the distance they could cover on a six-minute walk test. This discovery gave Dr. Hare and his colleagues the idea to use stem cell infusions to counter aging-related frailty.
A local biotech company is now developing an experimental therapy for aging-related frailty based on their work. Meanwhile, Dr. Hare and others affiliated with ISCI have continued studying mesenchymal stem cells as potential treatments for heart disease and many other conditions.
ISCI is now running six clinical trials testing them against diabetes, stroke, Alzheimer’s disease and cardiac disorders. Other trials are investigating therapies based on induced pluripotent stem cells (iPSCs) or cardiac stem cells, respectively, on inherited retinal disorders and severe heart defects in infants. These therapies account for eight of the approximately 17 investigational products ISCI has produced across its disease areas, or platforms.
Translational Experience
ISCI can undertake investigator-initiated clinical trials like these because it has its own means for developing and manufacturing the experimental therapies: an in-house cell manufacturing program, the Clinical Research Cell Manufacturing Program widely referred to as the GMP, or good manufacturing practices, lab.
Directed by Aisha Khan, a Ph.D. candidate, the GMP lab supports clinical and preclinical studies both at the university and at biotech companies that seek its assistance. As its name suggests, the GMP facility provides researchers with stem cells and other biological products, such as dendritic cells for use in immunotherapy and viral vectors that deliver gene therapy.
For ISCI member Alfonso Sabater, M.D., Ph.D., associate professor of clinical ophthalmology at Bascom Palmer Eye Institute and director of Bascom Palmer’s Corneal Innovation Lab, the GMP has provided support both in the lab and navigating FDA regulatory expectations.
A cornea and external diseases specialist, Dr. Sabater and his colleagues are developing an off-the-shelf therapy derived from human plasma to restore damage to the cornea caused by dry eye disease. This common condition can become particularly severe in people with autoimmune conditions, even leading to loss of vision.
“Tears are an ultra-filtered product of plasma. What we’re doing is trying to provide the patient with something that is as close as possible to a natural tear,” Dr. Sabater said.
The FDA has approved very few biologic (or biologically derived) therapies for the cornea for use commercially or in clinical trials. In seeking to translate this product for clinical use, his team leaned heavily on Khan’s expertise. While GMP staff tested and validated the product, her expertise ensured it met the FDA’s expectations for biologics.
“ISCI and specifically the GMP have been very supportive,” said Dr. Sabater, and he and his colleagues are now seeking approval to conduct a clinical trial in Mexico.
Collaboration is a routine part of belonging to ISCI.
“We know that other labs may be running the same experiments with other types of tissue or cells, so we can approach them with questions, and vice versa,” Dr. Sabater said. “It’s a constant interaction.”
Foundational Studies
Simultaneously, research at ISCI pushes the boundaries of basic science in ways that can, in time, lead to groundbreaking new therapeutics. One promising area of research has been exosomes, membrane-bound packets of signals released by cells, including stem cells.
With collaboration from Khan and the GMP facility, a team led by ISCI member Karen Young, M.D., a professor of clinical pediatrics at the Miller School, has studied exosomes as a potential therapy to prevent premature infants from developing bronchopulmonary dysplasia (BPD), a chronic breathing disorder with major public health implications. BPD can cause preterm infants to grow poorly and develop pulmonary hypertension, neurodevelopmental delays and hearing defects. Infants who survive BPD and its complications still face an increased risk of cardiopulmonary disease into adulthood.
Dr. Young and her team, along with Korean collaborators, are now awaiting approval from the FDA to conduct a pilot trial testing the feasibility of exosome therapy.
“There is currently no cure for BPD. If we can fix the problem early, we can save lives and even improve population health later on,” Dr. Young said.
Like the stem cells that release them, exosomes have many potential applications in medicine. Dr. Hare and his colleagues now know they were responsible, at least in part, for the rejuvenation seen in heart failure patients. Researchers at ISCI have received funding from the National Institutes of Health to test two types of exosomes’ capacity to repair damage caused by heart attacks.
In other basic studies, ISCI-affiliated researchers are using iPSCs to grow small, three-dimensional structures that resemble organs like the heart and brain. These organoids allow scientists to study organ development and offer new possibilities for replacing damaged tissue, such as that lost to a stroke.
For example, a collaborative effort with Stefan Kurtenbach, Ph.D., director of ISCI’s pluripotent stem cell laboratory and a research assistant professor of ophthalmology at Bascom Palmer, has developed organoids from patients with genetic forms of heart failure, allowing the researchers to study the affected hearts in early development.
Therapies of the Future
Dr. Hare predicts that, within the next five to 10 years, doctors in the United States will be able to prescribe stem-cell based therapies for numerous conditions.
“This is because of the foundational contributions programs like ISCI have made,” he said.
Although still experimental, stem cell-based therapies are part of a major shift in the paradigm that governs therapeutic development — away from treating disease by addressing single defects and toward promoting health in general, according to Dr. Hare.
“Not only can stem cells have therapeutic effects, but they seem to make the person, the whole person, healthier,” he said.
Tags: Aisha Khan, Bascom Palmer Eye Institute, Dr. Alfonso Sabater, Dr. Joshua Hare, Dr. Karen Young, Dr. Stefan Kurtenbach, exosomes, Interdisciplinary Stem Cell Institute, mesenchymal stem cells, stem cell therapies, stem cells