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Introduction¹

Regenerative medicine holds the potential to create living, functional cells and tissues that can be used to repair or replace those that have suffered potentially irreparable damage due to disease, age, traumatic injury, or genetic and congenital defects. The field of regenerative medicine is broad and includes research and development components of gene and cell therapies, tissue engineering, and non-biologic constructs. Although regenerative medicine has the potential to improve health and deliver economic benefits, this relatively new field faces challenges to developing policies and procedures to support the development of novel therapies that are both safe and effective. Additionally, there is hope that in light of increasing health care costs, regenerative medicine therapies may help reduce the total costs of patients care, even if the treatments are expensive at the outset.

The potential applications of cellular therapies are broad, ranging from the use of islet cell transplantation and regeneration to cure type 1 diabetes, to regenerative neurobiology approaches to treat injuries and degenerative diseases like spinal cord injury and amyotrophic lateral sclerosis (Feldman et al., 2014; Shapiro et al., 2000). Other areas of ongoing cellular therapy research include restoring vision through cell regeneration in the retina, repairing or restoring function in the musculoskeletal system, and improving or restoring function in various organs, including the heart, liver, lungs, and kidney (Trounson and

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¹ The planning committee’s role was limited to planning the workshop. The Proceedings of a Workshop has been prepared by the rapporteurs as a factual account of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They should not be construed as reflecting any group consensus.

McDonald, 2015; Tsukamoto et al., 2016). Although novel research findings in regenerative cellular therapies are promising, it is possible that they might benefit from a deeper understanding of basic biological concepts underlying the differentiation, engraftment, behavior, and survival of implanted cells in vivo. Such knowledge may help researchers address the scientific and technical hurdles related to assessing and ensuring successful long-term outcomes of cell therapies, controlling cell differentiation, and refining processes for production on a scale that is commercially sustainable and yields quantities of product that have the potential to be clinically effective. Some areas of regenerative medicine, such as hematopoietic stem cell transplants for the treatment of blood cancers, have experienced success in treating patients, and lessons and best practices could potentially be applied to other areas of research (Chhabra et al., 2016). It is also possible that increased communication and collaboration across fields may facilitate the sharing of these lessons to inform and advance ongoing research.

Current cellular therapies in regenerative medicine use several delivery approaches, including the introduction of cells that have been modified, expanded, or genetically manipulated into diseased tissue, with or without supporting biologic or nonbiologic materials such as key signaling molecules or scaffolding to facilitate the delivery and success of these therapies. (Researchers use the term “expand” to mean increase the number of cells through cell division.) Much of the research on these approaches is carried out using in vitro or rodent models, neither of which closely mimics the complex environment of the human body. Translating promising research from these models into clinical studies is a challenging process, and, as the field matures, there may be opportunities to develop guidelines for the safe and proper use of regenerative medicine advances, to highlight translational barriers, and to explore the regulatory environment. Potential challenges surrounding the process of characterizing cells and defining the critical quality attributes that cells and cell products must meet throughout the regulatory and manufacturing processes and maintain over time, also exist. Additionally, the study and use of regenerative medicine therapies are complicated by the ethical and social debate surrounding the use of adult, embryonic, and induced pluripotent stem (iPS) cells as well as cell products such as exosomes and hybrid devices.

During the first half of 2016, the National Academies of Sciences, Engineering, and Medicine’s Health and Medicine Division launched the Forum on Regenerative Medicine to highlight and discuss important scientific and policy issues that are emerging in this relatively nascent field. The forum members spent time considering many of the challenges facing the field.

On October 13, 2016, the Forum on Regenerative Medicine hosted its first public workshop with the goal of developing a broad understanding of the opportunities and challenges associated with regenerative medicine cellular therapies and related technologies. Stakeholder groups, including research scientists, clinicians, and representatives from patient groups and industry, presented their perspectives and participated in discussions during the workshop, which focused on an exploration of the state of the science of cell-based regenerative therapies within the larger context of patient care and policy. The specific workshop objectives are listed in Box 1-1. The statement of task for the workshop may be found in Appendix C.

OVERVIEW OF THE WORKSHOP

In order to demonstrate the breadth of the field and highlight advances in areas that are further along than others in terms of developing therapies that are safely available for patients, each session of the workshop focused on a different tissue or organ system: skin and musculoskeletal tissues, hematology and immunity, neurological and ophthalmological tissues, cardiovascular and lung tissues, and renal tissues. In each session, experts discussed the state of the science of regenerative medicine

in that particular area of research and identified challenges and successes. Several sessions also included a patient perspective. Following the presentations in each session, the speakers convened as a panel, highlighting common themes that had emerged during the day and reflecting on ways to address challenges and move the field forward in order to bring new therapies to patients. Although the presentations were divided by tissue area, the workshop was designed to encourage cross-fertilization and to highlight shared challenges. Cynthia Dunbar, the workshop co-chair and president of the American Society of Gene and Cell Therapy, asked presenters and participants to focus on describing the gaps in basic scientific knowledge, identifying resources that did or would help move regenerative medicine forward, and discussing common challenges such as reproducibility and standardization.

There are a number of factors that are coming together to increase the power and success of regenerative medicine, said Lorenz Studer, the keynote speaker and director of the Center for Stem Cell Biology at the Memorial Sloan Kettering Cancer Center. First, he said, while existing therapies such as bone marrow transplantation and skin grafts have shown what is possible for cell-based therapies, a number of therapies are on the horizon, such as iPS cells, which are adult cells that are reprogrammed to have the capacity to give rise to any type of cell in the body. Developing the properties of the right cell to use, whether in vitro or in vivo, has been an important factor contributing to success, with promising therapies emerging in the areas of macular degeneration, spinal cord injury, and type 1 diabetes. Second, Studer said, access and scalability are likely to be keys to the field’s eventual success. Recent advances in cell culture and manufacturing have increased the ability to scale up cell production, allowing millions or billions of cells to be generated, he said, but more research is needed. Third, he said, it will be important to use proof-of-concept studies to address unmet clinical needs. As industry recognizes the unmet needs of patients and the enormous potential of cell-based therapies, commercial investment in the area of regenerative medicine will rapidly increase, creating more opportunities for research to advance. Finally, Studer emphasized the importance of using robust animal models to move the field forward.

Studer listed some of the common shared problems in the field of regenerative medicine, some of which related to his ideas about factors that contribute to success. One major challenge, he said, is getting the right cell to the right target with the right function. This issue has been a bottleneck in the process of turning hypotheses into clinical therapies,

Studer said, but he added that this challenge is on the brink of being overcome in many diseases. Another challenge is understanding how to control cell maturation. In many cases, introduced pluripotent cells mature at a slower rate, which can not only delay the point at which they become clinically effective, but potentially create safety issues as well. Developing accurate models for testing therapies is critical; however, Studer said, current animal models often do not match the necessary physiology well enough to predict the effects of a therapy in the human body. For example, a small animal whose heart beats at 500 beats per minute does not serve as a good model for cardiac therapies for humans. The difficulty of finding an appropriate animal model, Studer suggested, may be eased in the future by the development of functional organoid-like structures, which could mimic organs and microenvironments in the human body. Also, cell-based therapies must overcome immunological barriers. Studer suggested several future possibilities for creating immunological compatibility, including using allogeneic off-the-shelf products, using patient-derived cells, building human leukocyte antigen (HLA)-matched cell banks, and developing universal donor cells. In addition to the scientific issues, Studer said, other logistical challenges remain, including the regulatory uncertainties surrounding cell-based therapies due to their complexity and inability to rely on established pathways, the lack of manufacturing experience in academia, and the lack of incentives for academics to pursue translational medicine.

Studer discussed some of these issues within the context of his own work on Parkinson’s disease. Motor symptoms of Parkinson’s are caused by the loss of dopaminergic neurons. The current therapeutic approach is to provide the drug L-dopa, which is taken up by cells and converted into dopamine; however, this approach becomes less effective over time. Studer’s team has attempted instead to replace the affected nerve cells, using pluripotent cells to make dopaminergic neurons. The team has had success using this approach in a mouse model of Parkinson’s. They grafted pluripotent cells into the mouse brain and demonstrated that the transplanted cells not only produced dopamine, but also resulted in an improvement in Parkinson’s symptoms.

Studer said that he and his team have faced a number of challenges in this line of work. First, it has taken an enormous amount of time; he has worked on this approach for 22 years, and it is still not yet a commercially available clinical therapy. Studer’s work on Parkinson’s began in 1995 and focused on fetal dopamine grafting in patients with the disease. Over the course of his research, further testing on other types of

cells indicated that pluripotent cells were more effective at making dopaminergic neurons, but it was not until 2011 that Studer’s team finally had a proof of concept for human cell-derived dopaminergic neurons. As of 2016, Studer’s lab had produced approximately 1,000 doses of human pluripotent stem cells using good manufacturing practice (GMP) standards, keeping them in frozen storage for later use in humans. In addition to this long period of research, other challenges that the team faced included

• developing an understanding of the mechanism of action of the therapy;
• adapting the cells to a GMP protocol, including creating a protocol that allows for the freezing and thawing of neurons while retaining viability and ensuring the shelf-stability of the cells;
• defining the cellular product by establishing functional cellular markers; and
• obtaining necessary expertise, resources, and regulatory approvals to manufacture cells.

Looking toward the future of regenerative cellular therapies, Studer pointed to several areas where he predicted that advances in science and technology will accelerate the progress of regenerative medicine. He suggested, for instance, that technologies that allow the better characterization of cell products will help researchers more clearly define their cells and improve the production of many different cell types. Another example of an emerging technology is the organoid, an organ-like structure made up of multiple cells and resembling whole organs; in the near term, it can be used to model disease, but it could also be used as a therapy for tissue replacement in the future (Lancaster and Knoblich, 2014). Studer also predicted that enhanced technologies to assess therapeutic effects in vivo will be critical to approaches that depend on manipulating and controlling cells in vivo. Understanding and controlling the maturation of cells, he said, is another issue that must be addressed, and it will require a thorough understanding of the mechanisms of cells.

Studer offered a suggestion of where the field may be in 5 years. Given the current state of the field and new scientific developments, he predicted that there will be a few products at the level of market approval, with many products in early-stage trials. While regenerative medicine holds promise, he said, scientists and other stakeholders should be careful to convey realistic expectations to patients and the public and to

make sure that new therapies are supported by strong scientific evidence. Studer said that he is concerned that poorly designed studies could move forward and negatively affect the entire field of regenerative medicine. Conducting high-quality research and moving the field forward will require collaboration and investment in the translational research pathway, he said. Translational research career paths should be created and included within academia, and grants and investments should be made to fund the translation of basic research into experimental clinical therapies, he suggested. In addition, he said, collaboration with regulators will be important since there is not an established pathway for the development of regenerative therapies. Patient and provider communication and involvement are critical, both to advancing the field and to preventing unrealistic expectations, Studer said.

ORGANIZATION OF THE PROCEEDINGS OF A WORKSHOP

Following this introductory chapter, Chapters 2 through 6 examine the state of the science in research and novel applications of regenerative medicine, discuss the obstacles that hinder progress as well as the elements that may contribute to success, and identify opportunities to move the field forward for various tissues and organ systems.

Chapter 2 explores the state of the field in regenerative medicine for skin and musculoskeletal tissues. Speakers with expertise in these tissue areas highlighted how successes in their fields may inform other areas of research and discussed the emerging challenges associated with manufacturing and scaling up treatments to be effective at a clinical level.

Chapter 3 describes how the field of hematology has used cellular therapies to treat immunological and hematological conditions and how lessons learned from those advances have informed the field of regenerative medicine as it continues to develop. Speakers on the hematology and immunity panel shared their views on the state of the science in hematopoietic stem cell transplantation, gene editing, and T cell therapies.

Chapter 4 delves into the scientific and clinical advances in regenerative medicine for neurological and ophthalmological tissues. Speakers on the neurological and ophthalmological panel explored the state of the science for regenerative therapies designed to treat a range of conditions including age-related macular degeneration and spinal cord injury.

Chapter 5 summarizes the presentations and discussions during the panel on cardiovascular and lung tissues. Speakers in the session shared

their insights on recent advances in the field, discussing in vivo cellular reprogramming, the therapeutic potential of exosomes, and the development of and uses for organoid-like structures.

Chapter 6 explores the state of the science and the potential applications of regenerative medicine for renal tissues. The panelists discussed the prevalence of renal failure, polycystic kidney disease, and emerging technologies related to organoids.

Chapter 7 offers some reflections by a panel of stakeholders on the common themes that emerged during the workshop along with a look toward the future of cell-based regenerative medicine approaches.