Cellular Therapies for Retinal Disease Steven D

Cellular Therapies for Retinal Disease Steven D. Schwartz Aaron Nagiel Robert Lanza Editors

Cellular Therapies for Retinal Disease A Strategic Approach

Foreword by Mark S. Blumenkranz Editors Steven D. Schwartz Aaron Nagiel Retina Division Chief Retina Division Department of Ophthalmology Department of Ophthalmology Ahmanson Professor of Ophthalmology Stein Eye Institute Stein Eye Institute David Geffen School of Medicine at UCLA David Geffen School of Medicine at UCLA Los Angeles, CA, USA Los Angeles, CA, USA

Robert Lanza Head of Astellas Global Regenerative Medicine Chief Scientific Officer at the Astellas Institute for Regenerative Medicine Marlborough, MA, USA

ISBN 978-3-319-49477-7 ISBN 978-3-319-49479-1 (eBook) DOI 10.1007/978-3-319-49479-1

Library of Congress Control Number: 2017943126

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This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword

We all look forward to the day when low cost personalized genomics to identify persons at high risk and some combination of small molecules, customized proteins, or gene therapy will severely reduce the incidence or entirely prevent blindness caused by the degeneration of ocular tissues. Unfortunately at the present time, although great strides in all those areas are being made, we are still left with limited options to treat the most severely affected persons with a wide variety of diseases including atrophic age-related macular degeneration, many inherited retinal dystrophies, and acquired optic nerve disease including glaucoma to name a few. But hope is on the way with the possibility of replacement of irreversibly diseased or absent tissues, including the retinal pigment epithelium, photoreceptors, and other neurons, with func- tionally active cells using the techniques of modern regenerative medicine. The biologic basis for these forms of treatment including the use of stem cells of various origin and degree of differentiation, and practical considerations including the use of scaffolding systems and novel microsurgical tools to enhance engraftment are all addressed in this book, which is one of if not the first on the subject and a welcome addition to the literature. This volume contains chapters from investigators around the world working in these areas and is edited by translational clinician scientists known for their contributions to ocular regenerative medicine. Robert Lanza is widely acknowledged as one of the fathers of the field of applied stem cell biology. His important collaborations with Drs. Steven Schwartz and Aaron Nagiel at the Jules Stein Eye Institute have led to the first influential publications in the Lancet of the use of differentiated stem cell-derived retinal pigment epithelium (RPE), for the treatment of geographic atrophy (GA) of the RPE related to age-related macular degeneration in older adults and Stargardt macular dystrophy in juveniles and young adults. Where there is still much to be learned about the long-term safety and efficacy of these efforts, the early results show some promise. Other chapters include the use of monolayers or scaffolds to implant cells, as well as supra-choroidal delivery systems. While much of the book is devoted to the treatment of retinal disease, there are well-written chapters addressing the possibility of cell transplantation techniques for glaucoma and early research efforts in disease modeling with affected stem cells that are able to be studied more effectively in vitro than by other methods. To be sure these efforts are still in the earliest stages of development and much more needs to be done before we even begin to talk about the possibility of their becoming standard of care. But every journey begins with a single step and the authors are to be congratulated for a timely volume that lays out the potential promise for this approach to better understanding and treating the most severe forms of ocular degenerative disease.

Mark S. Blumenkranz, M.D., M.M.S. HJ Smead Professor of Ophthalmology Emeritus, Stanford University Stanford, CA, USA

v Preface

As a graduate student in 1962, John B. Gurdon created live tadpoles after transplanting nuclei from frog intestinal epithelial cells into enucleated eggs. Thus began 50 years of work in stem cell research culminating in the 2012 Nobel Prize, awarded to Gurdon and Shinya Yamanaka for their contributions to the field. Research in regenerative medicine has progressed inexora- bly due to the exceptional promise it holds for understanding and potentially treating a variety of otherwise untreatable medical conditions. Some of these therapies are already being studied in patients, and many others are on the horizon. Alongside this transformative, exponential increase in regenerative medicine research, dur- ing the last 50 years we have witnessed an incredible expansion in our knowledge and treatment of retinal disease. Beginning with the advent of fluorescein angiography and ophthalmic lasers in the 1960s, we now find ourselves in an extraordinarily rich scientific and clinical landscape with widespread use of targeted biologic therapeutics, high resolution optical coher- ence tomography, ultra-widefield fundus imaging, and remarkable advances in vitreoretinal surgery. There is more to come. We are at the dawn of an era of cellular and gene therapy approaches that may provide legitimate hope for many untreatable retinal conditions affecting millions of people worldwide. These individuals are the inspiration for this book. Cellular Therapies for Retinal Disease: A Strategic Approach will systematically address the potential of cell-based therapies for the treatment of several retinal disorders for which there are no known treatments today. Rather than utilizing a disease-centric approach to this topic, this book will focus on strategies for creating, transplanting, and studying the cells. Accordingly, the book is divided into three parts:

Part I Cell Replacement Therapy Part II Cell-Based Neuroprotection Part III Disease Modeling Using Induced Pluripotent Stem Cells

In many retinal disorders, dysfunction and loss of particular retinal cell types is a common endpoint in disease pathogenesis. Transplanting replacement cells remains an attractive, “one size fits all” therapeutic ideal, as this approach may be agnostic to the molecular and cellular mechanisms underlying given conditions. For example, the retinal pigment epithelium (RPE) loss in dry age-related macular degeneration (AMD) and Stargardt disease might be addressed with RPE transplantation despite disparate pathophysiologies. Part I describes various aspects of cell replacement therapy for retinal diseases such as AMD, Stargardt disease, and glaucoma. This includes the use of embryonic and induced pluripotent stem cells to produce RPE and retinal ganglion cells, surgical techniques for subretinal transplantation, and scaffold materials to provide support for RPE monolayers. Part II contains two chapters demonstrating the use of cells for neuroprotection and trophic support of existing retinal cells. Rather than replacing retinal cells, this therapeutic strategy relies on stem cells to release trophic signaling factors that may sustain surviving cells and halt ongoing cell loss in slowly degenerative diseases such as dry AMD and retinitis pigmentosa. Part III showcases some of the most promising avenues for retinal research today. Induced pluripotent stem cells derived from skin fibroblasts or

vii viii Preface peripheral blood leukocytes can be derived from patients with any retinal disease and then differentiated into specific retinal cell types or multicellular retinal organoids to recreate the patient’s condition in the laboratory. A powerful research paradigm that could allow us to model human retinal disease and test treatments in a patient-specific, high-throughput fashion, this approach may facilitate important therapeutic interventions. Each chapter fleshes out the latest advances in cellular therapy with highly esteemed authors contributing from around the world. The goal of this book is to not only update the retinal physician or laboratory scientist on the current state of the field, but also bring together leaders in the field under the umbrella of this book. This is an age of increasingly collaborative and complex science, and a team effort will be necessary to develop novel treatments for retinal disorders. As editors of this text, we are compelled to emphasize the importance of rigorous research, scientific methodology, and responsible communication particularly in this era of uncurated, non-peer-reviewed internet-based hyperbole. As scientists and clinicians, it is our privilege to explore the fundamentals of regenerative biology and try to translate knowledge into clinically meaningful interventions that may reduce human blindness and suffering. Along with this privilege comes the responsibility to protect the public, our patients, and even health care providers from misinformation and those who might take advantage of the excitement surrounding “stem cell therapies.” The editors owe a deep gratitude for the support of the leadership, faculty, and staff at UCLA’s Stein Eye Institute, UCLA’s Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, and the universities and eye institutes of the many authors who contrib- uted to this book. Furthermore, on behalf of Drs. Schwartz and Nagiel, we wish to singularly thank Bob Lanza for his inspirational work and leadership. Importantly, encouragement from the American Academy of Ophthalmology, the Retina Society, the Macula Society, the American Society of Retina Specialists, and the Pine Ridge Eye Study Club must be men- tioned. In addition, this endeavor would not have been possible without the assistance of Michael Koy, Bibhuti Sharma, and Aleta Kalkstein at Springer, who guided us and the authors flawlessly through the production process. Lastly, and most importantly, we dedicate this book to our patients and our families from whom we constantly draw strength.

Los Angeles, CA, USA Steven D. Schwartz, M.D. Los Angeles, CA, USA Aaron Nagiel, M.D., Ph.D. Marlborough, MA, USA Robert Lanza, M.D. Contents

Part I Cell Replacement Therapy

Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cell Transplantation for Retinal Degeneration �� 3 Ninel Z. Gregori, Carlos A. Medina, Mira M. Sachdeva, and Dean Eliott Stem Cell-Derived RPE Transplantation: The Feasibility and Advantages of Delivery as Monolayers �� 19 Odysseas Georgiadis, Lyndon da Cruz, and Peter Coffey Induced Pluripotent Stem Cell-Derived Autologous Cell Therapy for Age-Related Macular Degeneration �� 33 Vladimir Khristov, Balendu Shekhar Jha, Aaron Rising, Yichao Li, Haohua Qian, Arvydas Maminishkis, Juan Amaral, Maria Campos, and Kapil Bharti Scaffolds for Cell Transplantation �� 45 Meena S. George, Hossein Nazari, Debbie Mitra, Dennis Clegg, David R. Hinton, and Mark S. Humayun Surgical Approaches for Cell Transplantation in Cell Replacement Therapy �� 55 Priya Sharma, Jayanth Sridhar, and Carl D. Regillo Cell Transplantation Therapy for Glaucoma �� 65 Xiong Zhang, Praseeda Venugopalan, and Jeffrey L. Goldberg

Part II Cell-based Neuroprotection

Autologous Bone Marrow-Derived Cell Therapies for Retinal Disease �� 79 Elad Moisseiev and Susanna S. Park Subretinal Delivery of Cells via the Suprachoroidal Space: Janssen Trial �� 95 James S. Baldassarre, Anthony Joseph, Michael Keane, and Jeffrey S. Heier

Part III Disease Modeling Using Induced Pluripotent Stem Cells

“Disease in a Dish” Modeling of Retinal Diseases �� 107 Huy V. Nguyen and Stephen H. Tsang Retinal Organoids: An Emerging Technology for Retinal Disease Research and Therapy �� 117 Jennifer G. Aparicio, Dominic W.H. Shayler, and David Cobrinik

Erratum to: Stem Cell-Derived RPE Transplantation: The Feasibility and Advantages of Delivery as Monolayers �� E1 Index �� 139

ix Contributors

Juan Amaral, M.D. National Eye Institute, National Institutes of Health, Bethesda, MD, USA Jennifer G. Aparicio, Ph.D. Division of Ophthalmology, Department of Surgery, The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA James S. Baldassarre, M.D. Janssen Cell Therapy, Janssen R&D LLC, Spring House, PA, USA Kapil Bharti, Ph.D. Unit on Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, MD, USA Maria Campos, M.D. National Eye Institute, National Institutes of Health, Bethesda, MD, USA Dennis Clegg, Ph.D. University of California, Santa Barbara, Molecular, Cellular and Developmental biology, Center for Stem Cell Biology and Engineering, University of California, Santa Barbara, CA, USA David Cobrinik, M.D., Ph.D. Division of Ophthalmology, Department of Surgery, The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA Development, Stem Cells, and Regenerative Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Peter Coffey, Ph.D. Institute of Ophthalmology, University College London, London, UK Lyndon da Cruz, Ph.D. Vitreoretinal Surgery, NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London, UK Dean Eliott, M.D. Retina Division, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Meena S. George, M.D., Ph.D. USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Odysseas Georgiadis, M.D. Vitreoretinal Clinical Research, Moorfields Eye Hospital, NHS Foundation Trust, London, UK Jeffrey L. Goldberg, M.D., Ph.D. Byers Eye Institute at Stanford University, Palo Alto, CA, USA

xi xii Contributors

Ninel Z. Gregori, M.D. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Jeffrey S. Heier, M.D. Ophthalmic Consultants of Boston, Boston, MA, USA David R. Hinton, M.D. USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Mark S. Humayun, M.D., Ph.D. USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Balendu Shekhar Jha, Ph.D. Unit on Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, MD, USA Anthony Joseph, M.D. Ophthalmic Consultants of Boston, Boston, MA, USA Vitreoretinal Surgery and Disease, Ophthalmic Consultants of Boston, Boston, MA, USA Michael Keane, M.S. Janssen Cell Therapy, Janssen R&D LLC, Spring House, PA, USA Vladimir Khristov, B.S. Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, Bethesda, MD, USA Yichao Li, M.S. National Eye Institute, National Institutes of Health, Bethesda, MD, USA Arvydas Maminishkis, Ph.D. Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, Bethesda, MD, USA Carlos A. Medina, M.D. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Debbie Mitra, Ph.D. USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Elad Moisseiev, M.D. Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, CA, USA Hossein Nazari, M.D. University of Texas Medical Branch, Ophthalmology, Galveston, Texas, USA Huy V. Nguyen, M.D. Massachusetts Eye and Ear Infirmary, Boston, MA, USA Susanna S. Park, M.D., Ph.D. Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, CA, USA Haohua Qian, Ph.D. National Eye Institute, National Institutes of Health, Bethesda, MD, USA Carl D. Regillo, M.D. Midatlantic Retina of Wills Eye Hospital, Philadelphia, PA, USA Aaron Rising, Ph.D. Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, Bethesda, MD, USA Mira M. Sachdeva, M.D., Ph.D. Retina Division, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Priya Sharma, M.D. Wills Eye Hospital, Philadelphia, PA, USA Dominic W.H. Shayler, B.A. Division of Ophthalmology, Department of Surgery, The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA Contributors xiii

Development, Stem Cells, and Regenerative Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Jayanth Sridhar, M.D. Midatlantic Retina of Wills Eye Hospital, Philadelphia, PA, USA Stephen H. Tsang, M.D., Ph.D. Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University Medical Center, New York, NY, USA Edward S Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA Department of Pathology & Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA Praseeda Venugopalan, Ph.D. Byers Eye Institute at Stanford University, Palo Alto, CA, USA Xiong Zhang, Ph.D. Byers Eye Institute at Stanford University, Palo Alto, CA, USA

The original version of this book was revised. An erratum to this book can be found at DOI 10.1007/978-3-319-49479-1_11