“Regenerative medicine can help patients at any age, from premature babies to frail seniors,” said Pascal J. Goldschmidt, M.D., Senior Vice President for Medical Affairs, Dean of the Miller School of Medicine and CEO of UHealth. “We are taking a comprehensive approach to keeping humans as healthy as possible.”
From concept to reality
In the two decades since biologist William Haseltine, Ph.D., the founder of Human Genome Sciences, introduced the phrase in 1992, regenerative medicine has moved from concept to reality in many clinical fields. Researchers continue to learn how different types of stem cells can be used to stimulate the healing process for tissues and organs, and address issues related to the body’s immune system.
“When there is chronic damage to tissue involving the immune system, as in inflammation or heart disease, the body loses the ability to repair itself,” said Goldschmidt. “In other cases, the repair system becomes misguided as a result of mutations of the cell DNA, a process that can lead to cancer, especially when surveillance provided by the immune system is failing. Regenerative medicine changes that process and holds the potential to address acute injuries and chronic ailments, including those associated with aging.”
Stem cell therapy to reconstruct damaged tissues and prevent the negative impact of the passage of time on the human organism is already benefiting Miller School/UHealth patients with serious health problems.
“We have successfully taken concepts from the laboratory bench to the clinic,” said Joshua Hare, M.D., the Louis Lemberg Professor of Medicine, founding Director of the Interdisciplinary Stem Cell Institute (ISCI), Chief Science Officer and Senior Associate Dean for Experimental and Regenerative Therapies. “This is leading-edge 21st century medicine.”
Since its formation in 2008, ISCI has made significant advances in interdisciplinary stem cell research, production and clinical care, working closely with teams at the Diabetes Research Institute (DRI), Bascom Palmer Eye Institute, the Ear Institute, The Miami Project to Cure Paralysis, the Sylvester Comprehensive Cancer Center and other Miller School programs.
In a major step forward in patient care, ISCI recently launched the first alpha stem cell clinic on the East Coast of the U.S. (Alpha stem cell clinics originated in California because of that state’s $3 billion investment in stem cell therapies.) The Miller School’s Comprehensive Program in Regenerative Medicine (CPRM) is a multidisciplinary clinical service line offered through ISCI and the University of Miami Hospital. According to Clinical Director Alan W. Heldman, M.D., professor of medicine, the CPRM brings together experimental regenerative treatments in the form of clinical trials for a wide range of conditions, including heart failure, vascular disease, stroke, pulmonary disease, arthritis, burns, wounds and skin disorders, Crohn’s disease, pediatric neurological disease and frailty in the elderly.
“In more than a decade of work, we brought stem cell therapy from the basic laboratory to clinical demonstration of its safety and efficacy in the treatment of heart failure caused by myocardial infarction,” said Heldman. “The great results of our PROMETHEUS, POSEIDON, and TAC–HFT clinical trials established the capabilities of our center to treat heart disease using stem cells produced in our own facility at ISCI. Together with the team’s ongoing studies in vascular disease, wounds, pulmonary fibrosis, and other conditions, the future of the CPRM will be to extend what we’ve learned to realize the full potential of regenerative medicine in a wide range of acute and chronic illnesses.”
As a collaborative cross-departmental clinical resource unit, CPRM already has clinical trials under way in many of these areas, with plans to double the number of trials in the next three years. “By integrating the Miller School’s multidisciplinary resources, our regenerative medicine program provides convenient access for patients seeking the latest information about stem cell therapy, and for those who want to participate in cutting-edge clinical trials,” Hare said.
Developing new cell-based therapies
The Miller School is also an international leader in developing cell-based therapies in the fight against diabetes and spinal cord injuries (SCI) through a collaborative relationship involving the DRI, The Miami Project and ISCI, which produces precursor cellular products used by the institutes.
Stem cells in their embryonic and adult forms are among several types of precursor or progenitor cells that can replace themselves while repairing different types of damage to the body. For instance, mesenchymal stem cells (MSCs) can form new bone, cartilage or fat cells – an important regenerative quality for dermatologists and orthopaedic specialists – and nerve-derived Schwann cells may be able to help patients heal spinal cord injuries and regain function.
Today, Miller School clinicians are using stem cells for treatments from cradle to grave. For instance, stem cells collected from the placenta can be reinjected into very premature infants to improve their growth and development. Bone marrow transplants with cord blood cells have also helped children suffering from metabolic disorders, cardiovascular disease and other abnormalities due to a lack of certain enzymes. In addition, a cell-based clinical trial for autism is now being developed by an ISCI interdisciplinary team. “The tissues in children’s bodies generally have a greater capacity to incorporate injected cells than tissues in adults,” Goldschmidt said.
At the other end of the spectrum, patients with aging-related frailty, a medical syndrome affecting millions of people, are going to be enrolled in the CRATUS study which will test whether stem cell injections can ameliorate or even reverse some of the changes associated with aging. Noting that stem cells can reduce chronic inflammation that erodes the body’s repair mechanisms, Goldschmidt said, “In many cases, these seniors can resume walking, cooking and other daily activities, so they can enjoy a more independent lifestyle.” ISCI has received FDA approval and initiated patient enrollment in the study that will test the impact of MSCs in individuals suffering from age-related frailty. Some patients whose frailty is accelerated, as in cerebral palsy, will also be provided with a novel MSC regimen to help them live better, longer.
“Our vision has been to bring the best, most rigorous science and rigorous clinical trial approaches to advance the treatment of incurable diseases,” Hare said. “We are now seeing the benefits that cell therapy brings to patients.”
Here is a look at how the Miller School’s researchers and clinicians are collaborating to develop a world-class regenerative medicine program whose goal is curing, rather than merely treating, disease.
Heart disease, vascular disease and stroke
A pioneer in using stem cells to repair damaged hearts and restore their function, Hare is recognized worldwide for changing medical history through his work. “After decades of basic science research, we are close to proving that a painless single-time stem cell treatment can reverse the course of cardiac disease in some patients,” said Hare, who is co-chair of curriculum for the Research Education component of UM’s Clinical and Translational Science Institute. Under his leadership, ISCI is a member of the seven-center elite Cardiovascular Cell Therapy Research Network (CCTRN) of the National Heart, Lung, and Blood Institute (NHLBI).
One of the most exciting trials that will start soon derives from an idea developed by ISCI scientists, who showed that a mixture of stem cells – MSCs and cardiac stem cells – doubled the regenerative response in damaged hearts. The ISCI team has already received FDA approval for clinical trials of this new approach, which could enhance cell-based therapy for patients with congestive heart failure.
ISCI’s research team is also taking part in an international clinical trial to determine the effectiveness of genetically targeted enzyme replacement therapy for advanced heart failure. The gene therapy, led at UM by cardiologist Claudia Martinez, M.D., is designed to restore levels of an important enzyme called SERCA2a, which regulates the production of calcium ions needed for the contraction and relaxation of cardiac muscle cells. Patients with advanced heart disease may also benefit from stem cell therapy that would restore production of the SERCA2a enzyme. “We now have two options on the table that could be applied separately or combined, depending on the most effective approach,” Martinez said.
Hare says ISCI is dedicated to finding the answers to the most important basic questions in life science today: What are the properties that allow stem cells to differentiate into any cell type in the body, and also to reprogram other cells and repair their damaged tissue?
“While we started with the heart, we believe there is great potential for stem cell therapies in multiple organ systems,” Hare said, noting that ISCI is the only institute approved for clinical trials of a devastating lung disease – idiopathic pulmonary fibrosis. Marilyn K. Glassberg, M.D., associate professor of medicine and surgery and director of ISCI’s pulmonary platform, recently enrolled the first patient in this trial – the AETHER study – which uses MSCs as a cellular therapy to treat patients with pulmonary fibrosis, a devastating condition where the lungs become encased in scar tissues, and for which there is no cure today.
While the results must await conclusion of the trial, Hare is hopeful that stem cell therapies can lead to better outcomes. As he said, “Our team has been monitoring lung function very carefully in patients treated with stem cells for heart disease, and found that lung function actually improved with some stem cell treatment.”
The ISCI team, working in collaboration with the Vascular Disease Division, is also enrolling patients in a CCTRN– sponsored trial for peripheral vascular disease. And working with Dileep Yavagal, M.D., Director of Interventional Neurology and assistant professor of neurology, programs are planned in using the cells produced by ISCI for patients suffering from stroke.
Spinal cord injuries
Since the 1980s, The Miami Project to Cure Paralysis has been looking for ways to repair and regenerate the central nervous system, helping patients with spinal cord injuries, as well as traumatic brain injuries (TBIs) and disorders like Parkinson’s disease, and drawing on the Miller School’s multidisciplinary research and clinical resources.
“Our team is the best in the world in central nervous system injury and repair,” said W. Dalton Dietrich, Ph.D., Kinetic Concepts Distinguished Chair in Neurosurgery, Professor of Neurological Surgery, Neurology and Cell Biology, and Scientific Director of The Miami Project to Cure Paralysis. “Our scientists are trying to understand how to enhance the regeneration in nerves using genetic approaches, viruses, scaffolding materials and other strategies. We’re also undertaking basic science that’s fueling the clinical studies and trials.”
In 2013, physicians at The Miami Project to Cure Paralysis performed the first Food and Drug Administration-approved Schwann cell transplantations in two patients with new spinal cord injuries. Schwann cells play a crucial role in the repair of peripheral nerves, forming protective sheaths around the axons that transmit nerve impulses. The Phase 1 clinical trial is designed to evaluate the safety and feasibility of transplanting the participant’s own Schwann cells.
“We feel that Schwann cell transplantation, together with neuro-rehabilitation strategies, may be able to make a difference in the lives of people living with spinal cord injuries,” said Dietrich. “This trial, when completed successfully, will lay the critical foundation for future cell-based therapies.”
On the clinical side, Miller School physicians recently performed an innovative procedure on a patient who sustained a propeller cut through the sciatic nerve in her left leg in a boating accident. Concerned that the 26-year-old patient would never regain feeling and movement in her left leg, neurosurgeon Allan D. Levi, M.D., Ph.D., received FDA approval to transplant her own Schwann cells along with a nerve graft for her leg. This technique had never before been used to regenerate a damaged peripheral nerve. It will take months or even years to determine if the surgery was successful.
Other laboratory research at The Miami Project involves the use of cell therapies to promote the reorganization of the nerve system’s circuits and behavioral recovery. Recent studies have involved using a multineurotrophin – a protein that supports neuron repair – with mesenchymal stem cells and neural progenitor cells in order to support nerve repairs.
“One of our key areas of focus is regenerating axons — the signaling cells of the nervous system,” said Dietrich. “We are also developing neuroprotective and anti-inflammatory drugs that can make the local environment more supportive for nerve regeneration. Everything we do at The Miami Project to Cure Paralysis has the potential to impact not only nervous system injuries, but also other conditions, and to change the practice of medicine.”
Another field where the Miller School’s regenerative medicine program is making significant progress is in the development of cellular treatments for diabetes. Back in 1986, Camillo Ricordi, M.D., created the Ricordi Chamber, which isolates the insulin-making islet cells produced by the pancreas – a key step in transplanting those cells into patients with severe Type 1 diabetes, an autoimmune disease. Instead of transplanting the whole organ, clinicians insert the islets in the pancreas. Currently, about 50 percent of patients with transplants stay off insulin for five years, a rate comparable to those who have had a pancreas transplant. However, those patients need anti-rejection drugs so their immune systems don’t attack the newly transplanted cells.
Ricordi has also been working in the area of cellular repair, regeneration and reprogramming strategies that would eliminate the need for transplants and anti-rejection drugs in Type 1 diabetes. “We are studying the use of progenitor cells from a patient’s own pancreas to regenerate insulin-producing cells,” said Ricordi, who is Director of the University of Miami Diabetes Research Institute and Stacy Joy Goodman Professor of Surgery, Distinguished Professor of Medicine, Professor of Biomedical Engineering, and Microbiology and Immunology.
“We are also looking at trials using the donor’s bone marrow cells to replace the recipient’s immune system, as well as new materials to encapsulate and protect the islet transplants from the body’s immune system,” he added.
Through the international Clinical Islet Transplantation Consortium, Ricordi is developing the “BioHUB,” an islet transplantation platform that mimics the pancreas, and releases insulin in response to glucose, while protecting the transplanted islet cells from the body’s immune system. “We know that islet cells can restore natural insulin production with minimal risks,” he said. “The DRI BioHUB creates a physical environment for transplanted islet cells. It would allow for a transplant of encapsulated islets without immunosuppression drugs.”
Ricordi has also been a leader in international collaborative initiatives to harvest mesenchymal stem cells from adipose tissue, condense the cell suspension, and reinject those concentrated cells back into patients. Already in use in Europe for plastic and cosmetic surgery, this system has potential to treat diabetic ulcers, accelerate wound healing, and support the reconstruction of other tissues, according to Ricordi.
“We take a collaborative approach to building the Miller School’s regenerative medicine program,” Ricordi said. “The regenerative approaches we are developing for diabetes may have important future applications in other cellular therapies as well, in keeping with our focus on taking care of individual patients while developing a cure for millions of people worldwide.”
Orthopaedics is another field where stem cell therapies are being developed, to repair damaged bones, cartilage, muscles and joints. In addition, platelet rich plasma (PRP) and recombinant human Bone Morphogenetic Protein (rhBMP-2) are already in clinical use to accelerate wound healing and bone regeneration.
“There are many tissues that are traumatized from athletic activities or chronic orthopaedic disease processes,” said Lee Kaplan, M.D., professor of orthopaedics and Chief of UHealth Sports Medicine in the Miller School’s Department of Orthopaedics. “If we can stop that process of degradation, patients will be able to retain or even regain healthy functioning.”
For instance, knowing how the knee cartilage responds to a traumatic injury can help slow the process of arthritis with biological treatments, he added. “If we can address those types of injuries soon after they occur, we may be able to keep them from developing into chronic, painful problems.”
Kaplan directs the UHealth Sports Performance and Wellness Institute, which focuses on optimizing performance, injury care and prevention. He is collaborating with UM Biomedical Engineering in stem cell therapies to improve cartilage health, and with ISCI in looking at cellular healing pathways for ligaments and tendons. Kaplan’s team has already completed important research into the role of platelet rich plasma and MSCs in healing knee injuries and plans clinical trials for a variety of joint diseases using MSCs. This includes working with the Miller School’s John P. Hussman Institute for Human Genomics to identify genetic markers and obtain “real-time information” on how stem cells and PRP factors can help the healing process.
To further advance his work in orthopaedics, Kaplan plans to collaborate with Hare’s team in a program to use cell lines produced at ISCI that have already been shown to be safe in cardiac patients – an example of how breakthroughs in one discipline can advance other aspects of the Miller School’s regenerative medicine program.
Stem cell transplantation is an effective strategy for treating diseases of the immune system, as well as cancers in adult and pediatric patients, according to Stephen D. Nimer, M.D., professor of medicine, biochemistry and molecular biology, and Director of the Sylvester Comprehensive Cancer Center.
“One of the greatest advances in regenerative medicine is being able to treat and cure cancers and autoimmune disorders,” said Nimer. “Being able to regenerate a painful joint in a patient with rheumatoid arthritis, for instance, will make a tremendous improvement in that person’s long-term health and quality of life.”
Stem cell transplants can also help patients with amyloidosis, a disease where amyloid proteins produced in the bone marrow build up in the heart, kidneys, liver, spleen, nervous system and gastrointestinal tract. Patients with late-stage disease typically need an organ transplant to survive. “But if we don’t fix the bone marrow, it will continue to make the same unhealthy proteins and recreate the same problem,” Nimer said. “It is much better to regenerate the bone marrow and get to the root of the problem, while the protein buildup can still be reversed.”
In the future, cellular transplants may be able to help children with defective immune systems, adults with memory disorders, and patients of all ages with autoimmune problems. “These are all highly promising fields for regenerative medicine,” Nimer said. “New strategies to address these serious health problems may lead to far better outcomes.”
Cancers of the blood
Stem cells formed in the bone marrow provide a fundamental defense to fighting cancers of the blood. “Transplants of bone marrow stem cells have been the standard of care for decades for patients with high-risk blood cancers,” said Krishna Komanduri, M.D., professor of medicine, microbiology and immunology and the holder of the Kalish Family Endowed Chair in Stem Cell Transplantation and director of the Adult Stem Cell Transplant Program at the Sylvester Comprehensive Cancer Center. He is also medical director of the ISCI cellular production laboratory.
In October Komanduri’s team performed the program’s 100th stem cell transplant on a patient with multiple myeloma, a cancer of the plasma cells in bone marrow, infusing stem cells that had been previously harvested from the patient. The program treats patients from 17 to 75 years old with various types of cancer and hematological diseases. “Stem cell transplants are among the most complex medical procedures conducted at cancer centers,” said Komanduri. “They require a high level of clinical infrastructure as well as professional expertise at every stage in order to maintain a high level of clinical care.”
In addition to “autologous” transplants using the patient’s bone marrow cells, the Sylvester team regularly performs “allogeneic” transplants using stem cells from matched relatives, or unrelated donors. Both types of transplants are performed after a cancer patient receives chemotherapy or radiation therapy, killing the existing cancer stem cells in the bone marrow. A successful stem cell transplant helps restore the bone marrow’s ability to grow healthy blood cells, and also helps eliminate residual cancer cells.
“The transplanted cells include infection-fighting and cancer-fighting T cells from the donor as well as stem cells,” said Komanduri. “Modern transplant approaches have allowed us to reduce the toxicity of the chemotherapy and led to dramatic improvements in outcomes for patients with acute myeloid leukemia and other cancers.”
Komanduri is also studying “graft-versus-host disease,” in which T cells from the donor attack healthy tissues in the recipient. “We are working hard to study the immune system in transplant recipients to further improve treatment outcomes.”
Pediatric bone marrow transplants
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood and the most common cause of cancer-related death for children under the age of 19, because although ALL is chemosensitive at initial diagnosis it becomes highly resistant at the time of relapse (cancer recurrence). In addition, despite great strides made in the treatment of childhood leukemia over the past 30 years, a significant percentage of children with ALL and acute myeloid leukemia will require bone marrow transplants.
“In the past, none of those children would have survived, but today we can rescue at least half of them,” said Julio Barredo, M.D., professor of pediatrics, Director of Pediatric Hematology-Oncology, and Director of Sylvester Children’s Cancer Programs. “For pediatric patients with non-malignant diseases, such as sickle cell anemia, the success rates are well over 90 percent.”
Barredo says the transplant team’s ability to take advantage of the donor’s immune system to fight the child’s leukemia is one of the keys to better outcomes. “What really benefits a cancer patient is being able to transplant components of the immune system along with the bone marrow cells,” said Barredo, who focuses his research on the molecular mechanisms leading to cancer cell sensitivity and resistance to molecular targeted agents.
John Goldberg, M.D., another member of the pediatric team, is conducting clinical trials using novel cell-based vaccines to treat patients of all ages with cancer cells in the brain tissue called gliomas and for soft-tissue cancers called sarcomas. “Like a vaccine for the flu, we want to use stem cells to help the patient’s immune system recognize the cancer cells and fight the tumors,” Barredo said.
The Miller School’s pediatric bone marrow transplant program is the only one in South Florida capable of conducting innovative trials, with clinical operations at Holtz Children’s Hospital at Jackson Memorial Hospital. “Our program has experienced a 300 percent growth in volume in the past 18 months,” Barredo said. “We do transplants using the patient’s own cells, as well as sibling and unrelated donor transplants.”
The evolution of medicine
In the coming decades, regenerative medicine will play an increasingly important role in the delivery of clinical care – and the Miller School intends to be the front-runner. “This is one of the biggest evolutions in medical history,” Dean Goldschmidt said. “It’s comparable to the introduction of antibiotics in the 20th century or the discovery of DNA by Avery, MacLeod and McCarty during the Second World War.
“There is only so much you can do to treat injuries and diseases. As we learn how to regenerate cells and strengthen the body’s repair processes, we can make tremendous advances in improving clinical care and maintaining long-term good health.”
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