Cellular Therapies for Retinal Disease Steven D
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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 © Springer International Publishing AG 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cover illustration: Saravanan Karumbayaram, M.Pharm., Ph.D. Printed on acid-free paper 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 ocu- lar 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 tis- sues, 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 regen- erative 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 treat- ment 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 treat- ment 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