StemCell Therapy

Biotherapeutics

January 13, 2021

Regenerative medicine has contributed to patient care in 2020 more than ever before, bolstered by synergies in research, practice and education. Mayo Clinic's Center for Regenerative Medicine is at the forefront of a biotherapy revolution in which health care advances from treating disease to restoring health.

"The centrality of the body to regenerate itself is paving the way for new horizons in regenerative care. The triad of protecting against disease, preventing disease progression and promoting healing is at the core of the regenerative vision," says Andre Terzic, M.D., Ph.D., director of Mayo Clinic's Center for Regenerative Medicine. "To this end, the regenerative toolkit has grown more robust over the past year with new technologies now available to boost the body's ability to repair and restore health of an organ and importantly of the patient as a whole."

The convergence of research, practice and education, empowered by strong innovation and advanced biomanufacturing, is creating an increased level of readiness for applying validated regenerative science to new areas of health care, Dr. Terzic says.

Practice advancement

A deeper understanding of the biology of health and disease is driving the ongoing regenerative medicine evolution.

"The remarkable progress in science that is advancing our fundamental comprehension of both health and disease has guided the informed and responsible development of patient-ready curative strategies," says Dr. Terzic.

New discoveries at Mayo Clinic that may shape future practice include:

The largest regenerative medicine clinical trial to date for heart failure, spanning 39 medical centers and 315 patients from 10 countries, validated the long-term safety of stem cell therapy. The late-stage research found stem cell therapy shows particular benefit for patients with advanced left ventricular enlargement. This Mayo Clinic-led study offers guidance on which patients are most likely to respond to stem cell therapy for heart failure.

Mayo Clinic researchers uncovered stem cell-activated molecular mechanisms of healing after a heart attack. Stem cells restored the makeup of failing cardiac muscle back to its condition before the heart attack, providing an intimate blueprint of how they may work to heal diseased tissue. This research offers utility to delineate and interpret complex regenerative outcomes.

Mayo Clinic research discovered a molecular switch that turns on a substance that repairs neurological damage. This early research could bolster a therapy approved by the Food and Drug Administration, and that could lead to new strategies for treating diseases of the central nervous system such as multiple sclerosis.

The federal regulatory environment is making it possible to more seamlessly integrate new discoveries into the practice. The 21st Century Cures Act, for example, seeks to create an accelerated path to market for safe, validated procedures that could provide new therapies for patients with serious conditions.

Examples of how that new regulatory environment is accelerating discoveries into regenerative care at Mayo Clinic are:

With FDA permission, Mayo Clinic performs surgery before birth to correct a congenital defect known as spina bifida. Spina bifida is a condition in which the spinal cord does not close properly. Fetal surgery at Mayo Clinic to repair the spinal cord not only closed the spine, but also restored brain structure. Clinical experience to date, published in Mayo Clinic Proceedings, concluded that fetal surgery to treat spina bifida is effective at early healing of neurological structures. Mayo continues to evaluate this regenerative procedure.

Mayo Clinic has FDA permission for investigational new drug use in regenerative surgery aimed at restoring damaged knee cartilage in a single surgical procedure. Bits of a patient's cartilage are recycled and mixed with donor mesenchymal stem cells. Mesenchymal stem cells are adult stem cells derived from sources such as fat tissue or bone marrow. Much like filling potholes in a street, the cellular mixture repairs holes within the cartilage. Mayo Clinic is treating patients with this surgery and hopes to make it available to patients more broadly within the coming year.

Mayo Clinic promotes responsible adoption of validated procedures. An example of this ongoing effort is a regenerative procedure that augments standard surgery for cancer.

Mayo Clinic orthopedic oncologists are teaming with plastic surgeons to restore muscle strength after some cancer surgeries, particularly surgery to remove soft tissue sarcoma. Advancements in microsurgery are making it possible to transfer large muscle to close a surgical wound where it functions like the muscle lost to cancer. This so-called "oncoregenerative" surgery combines free muscle transfers with pain management and lymphatic reconstruction, while preventing damaged nerves and lymph nodes that can cause pain and swelling.

Regenerative medicine know-how is advancing immunotherapy options for cancer patients, including chimeric antigen receptor-T cell therapy (CAR-T cell therapy). CAR-T cell therapy seeks to unleash the power of the immune system by genetically modifying cells, equipping them to go on search-and-destroy missions to kill cancer. These engineered cells act like a living drug, continually working within the body to cure disease.

"On-demand regenerative immunity is being built against blood cancers and is advancing how hemato-oncologists treat lymphomas and leukemias. We hope that regenerative sciences will discover and perfect ways to expand this treatment approach to solid cancers, as well," says Dr. Terzic.

Biomanufacturing and supply chain readiness

Mayo Clinic is on the cusp of validating new advanced biomanufacturing facilities where it will engineer the latest cellular, acellular and gene therapies needed for regenerative care. In doing so, Mayo is establishing its in-house supply chain, ensuring quality, and potentially saving time and resources.

Center for Regenerative Medicine has increased supply chain readiness in 2020 in these ways:

Supported by active research and development programs, Mayo Clinic is poised to test acellular healing products known as exosomes in the first clinical trials. Exosomes are extracellular vesicles that are like a delivery service moving cargo from one cell to another, with instructions for healing. It's an example of the emerging field of nanomedicine. Nanodrugs are very small structures that contain enveloped proteins and genetic materials that can be targeted to exact tissues in need of repair.

"Over the past five years, we discovered the healing potential of exosomes, established the science, and ultimately figured out how to manufacture them so that they would meet strict quality standards. Now we are ready to take the important step of introducing them in human safety trials," says Atta Behfar, M.D., Ph.D., deputy director of translation for Mayo Clinic's Center for Regenerative Medicine. "I think the evolution into nanomedicine as a regenerative tool is major milestone. Compared to more traditional living alternatives, these biological messages can be easier to store, ship, analyze and even manufacture."

Exosomes are an example of how Mayo Clinic is manufacturing new healing products that, unlike living stem cells, can be stored at room temperature on-site for immediate use in a hospital or clinic

"Technologies that can be stored at room temperature on the shelf provide the ability to introduce regenerative medicine into new areas of practice such as heart attack and stroke, where therapies need to be delivered on an emergent basis," says Dr. Behfar. "As we move forward, this type of accessibility may help to facilitate adoption of biologics-based therapies and continue to broaden our ability to offer innovative cures to patients in need."

New 3D printing capabilities at Mayo Clinic in Arizona are providing options to improve laryngeal or vocal fold function. For example, 3D printing is providing new ways to close the gap between vocal folds for people with glottic insufficiency a common but difficult-to-treat condition that causes problems with speaking, breathing and swallowing. A 3D implant is printed to fit the exact patient-specific dimensions of the vocal folds and implanted into the voicebox, where it improves voice, swallowing and breathing.

Mayo Clinic in Florida launched the CAR-T Translational Research program that aims to expand regenerative immunotherapy products beyond blood cancers, potentially to neurological and autoimmune disorders. Clinical-grade biotherapies can be manufactured on-site, which potentially will lower the cost and increase patient access to regenerative immunotherapies such as CAR-T cell therapy.

Workforce proficiency

Educating future physicians, scientists and the broader health care workforce to provide the latest, most innovative regenerative medicine technologies is a key objective of the Center for Regenerative Medicine. That strategic priority is reflected in the regenerative curricula that are integrated across each of the five schools of Mayo Clinic College of Medicine and Science.

"We are educating regenerative medicine practitioners who are grounded in scientific knowledge to responsibly translate the latest innovations into patient solutions. They are becoming a trusted source of regenerative care," says Dr. Terzic.

Advancements in training the future workforce in regenerative medicine and science include:

Mayo Clinic graduated the first students in the doctoral research training program known as the Regenerative Sciences Training Program. Established in 2017, this program combines laboratory research with training that covers the complete spectrum of discovery to translation topics.

Mayo Clinic launched one of the first-ever doctoral tracks in regenerative sciences in Mayo Clinic Graduate School of Biomedical Sciences. The curriculum will embrace a training paradigm that includes fundamental cellular and molecular science principles, and transdisciplinary education in regulatory issues, quality control, entrepreneurial pathways, data science, medical sciences, ethics and emerging technologies. Applications opened in the fall, and the first students will be admitted in fall 2021.

In recognition of the scholarly identify of regenerative medicine, Mayo Clinic elevated regenerative medicine to a field of academic rank. Implementing academic ranks paves the way for attracting a new community of dedicated physicians, scientists and engineers focused on advancing regenerative medicine.

"Regenerative medicine touches all medical, surgical, radiology and laboratory medicine specialties across Mayo Clinic. Establishing this new academic rank is like opening a new chapter in medicine. It is a key differentiator for Mayo Clinic," says Dr. Terzic.

Advancements to watch for in 2021

The opening of two major manufacturing facilities in Rochester and Jacksonville, Florida, will propel Mayo Clinic to a new realm of biomanufacturing and supply chain management of therapeutics for rare and complex medical conditions. The two facilities are cornerstones of a coordinated biomanufacturing strategy that positions Mayo Clinic to deliver first-in-the-world therapeutics produced on-site for use in research and practice. Together with industry partners, Mayo will accelerate these new regenerative products toward the market to benefit Mayo Clinic patients and others around the world.

Here are some specific examples of things to watch for:

The Center for Regenerative Medicine's advanced biomanufacturing facility is nearing completion at One Discovery Square in Rochester. The new facility is equipped with current Good Manufacturing Practices capable of producing clinical-grade regenerative therapies that are easily accessible for clinical trials and patient care. Biomanufacturing will focus on tissue engineering, cellular, acellular and gene therapy products.

Construction is complete on the Center for Regenerative Medicine's advanced biomanufacturing facility in the new Discovery and Innovation Building at Mayo Clinic in Florida. When fully operational, it will deploy current Good Manufacturing Practices facilities where new patient-ready immunotherapies can be manufactured under strict sterile quality control measures that meet FDA guidelines. That could eventually increase patient access to CAR-T cell therapy and other regenerative immunotherapies through clinical trials. On site manufacturing will reduce cost and broaden the access for this curative technology to Mayo patients suffering from lymphoma.

Mayo Clinic will conduct first-in-human safety and dosing studies of exosomes noncellular structures that deliver healing to damaged cells and tissues. After discovering, scaling and manufacturing exosomes, Mayo will evaluate them in the first human trials for wound healing and tissue repair after a heart attack.

Mayo Clinic is on track to launch one of the first-ever living donor cartilage banks. Mayo Clinic orthopedics and sports medicine surgeons, in collaboration with the Center for Regenerative Medicine, have validated methods to collect and store living cartilage tissue that would otherwise be discarded after knee replacement surgery. The donor cartilage bank will dramatically reduce wait times for this valuable tissue used to repair knee damage in younger patients with cartilage and bone damage in their knee.

Regenerative procedures may trigger healing of diseased tissues in some patients, but those therapies may not work for others. One of the key riddles regenerative medicine research seeks to crack is how to target patients who are most likely to benefit from restorative therapies.

"With the assimilation of data sets, we hope to decode the attributes that define regenerative responsiveness. That is the holy grail of regenerative medicine right now," says Dr. Terzic.

As 2020 wraps up and 2021 begins, Mayo Clinic seeks to further its understanding of regenerative medicine, and make new approved therapies accessible and affordable for all patients, particularly those with unmet needs and those in underserved communities.

Dr. Terzic is the Michael S. and Mary Sue Shannon Director, Mayo Clinic Center for Regenerative Medicine, and Marriott Family Professor in Cardiovascular Diseases Research.

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Diverse ways regenerative medicine is advancing health care

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