Gene Therapy for Neurological Disorders PDF

Preface

It is difficult to know whether the apple that fell onto Newton's head was ripe or not; the fact is that it kindled Sir Isaac into action. Whether ideas are truly ripe or not at the time of their fall from the tree is only determined a posteriori. Thus, one of the important aspects that gene therapy has launched is new therapeutic approaches to the treatment of disease.

As illustrated in Figure 1, from humble beginnings in the early 1980s, gene therapy has progressed to establish professional societies throughout the world, specialty journals, international conferences, clinical trials, and the recent first commercialization of gene therapy in China in 2005 (1). As originally promised, cures of heretofore incurable diseases have come to pass: bubble boys have been able to leave their sterile bubbles and receive without fears the germ laden embraces of their parents (2). However, eating from the tree of knowledge has its price, and gene therapy, in spite of its successes, has fallen short of the magic bullet approach expected.

The side effects of this new therapeutic approach, which is part of the larger field of pharmacology, have thrown the news reporters into disarray. Society has found it difficult to balance the reports of new cures for so far untreatable diseases with the fact that the new therapies also can have side effects. We all would like to eat from the tree of knowledge without being banned from paradise. As the Bible has taught for generations, this is impossible in faith, as it is in science. The compromise must be to eat of the tree of knowledge (i.e., developing new therapeutic approaches), knowing, predicting, and being prepared for the fact that side effects will be part of the price to pay for the therapeutic advances.

Scientists, clinicians, clinical investigators, and other professionals have responded, as suggested by Orkin and Motulsky in 1996 (3), by returning to the lab benches to continue developing and expanding the rather simple, powerful, even once revolutionary idea of clinical gene therapy. This book provides the reader with an overview of some of the latest achievements in this field, results from the Orkin and Motulsky "return to the bench" injunction!

From the recognition of some of the most challenging limitations of gene therapy, i.e., the immune responses against viral vectors and transgenes, to novel developments, and clinical applications, the editors have worked hard to provide a picture as comprehensive as possible on the current developments of gene therapies for brain diseases. The book chapters review the latest developments in the construction and production of vectors to contain large transgenic constructs, such as the novel HSV-1 derived amplicons and iBAC vectors (Chapter 2, by Epstein, Chapter 5, by Lawler et al.) and high-capacity, helper-dependent adenoviral vectors (discussed in Chapter 1, by Zirger et al. and Chapter 13, by Castro et al.), or the replication-competent viral vectors, as well as the uses of vectors to treat brain tumors, chronic neurodegenerations such as Parkinson's (Chapter 9, by Torres et al.) and Alzheimer's disease, and the challenge of chronic pain, a particularly felicitous application of herpes simplex virus1 (HSV-1) derived vectors (Chapter 10, by Mata et al.). Also, the use of vaccination strategies to treat brain tumors (Chapter 14, by Wheeler and Black), and potentially Alzheimer's disease is described (Chapter 11, by Bowers and Federoff), and how this can be implemented using viral vectors, is presented in various chapters.

Since commissioning the initial chapters for this book, stem cells broke the sound barrier in the field of the neurosciences and, as basic knowledge, moved forward—so did the potential of their clinical applications. Even if stem cells have the great potential for replacing populations of highly differentiated cells, such as brain cells, the challenge remains to guide their differentiation. And the easiest manner of doing so is indeed the use of viral vectors to express specific factors to guide the differentiation of stem cells in predetermined directions. This is discussed in detail in many chapters throughout the book, but is central to Chapter 6 by Cortes and Breakefield.

The immune response has two sides. On the one hand it presents us with the most challenging topic in the field, having been most likely the cause of the failure of a number of clinical trials (Chapter 1, by Zirger et al.), while the therapeutic use of the immune system to actually treat disease, whether to eradicate brain tumors (Chapters 13, 14) or treat neurodegeneration (Chapter 11). Although most discussions on the immune system and gene therapy have compared challenges and positive effects, a more recent discussion involves the potential of utilizing immunosuppression to thwart early immune responses to allow viral vectors such as adeno-associated viral vectors (AAV), novel high-capacity adenoviruses, or heres simplex virus1 (HSV-1)-derived amplicons to deliver their therapeutic genomes to target cells without being attacked by the immune system (4). Finally, the potential of utilizing gene therapy to treat autoimmune brain diseases, a future challenge for neurological gene therapy, is discussed in Chapter 12, by Larocque et al.

Other developments, such as non-viral vectors that may take advantage of applications for which only short-term gene therapy may be the therapeutic target are discussed in Chapter 8, by Medina-Kauwe, and the potential targeting of astrocytes to treat brain diseases, is given in depth treatment in Chapter 7 by Imura and Sofroniew.

In the long run, gene therapy for brain diseases will be judged by its clinical results, and it is thus that the book ends with the clinical experience of Pulkkanen and Yla-Herttuala in Chapter 16. This group has performed some of the best designed clinical trials in gene therapy, including relevant comparative controls to judge the efficacy of their new therapies. Other clinical trials for neurodegenerative diseases such as Parkinson's disease (Chapter 7) or Alzheimer's disease (Chapter 8) have been tested or will be tested in Phase I clinical trials, but the recent nature of these studies, and their current plans for expansion to larger, controlled trials, is eagerly expected. It is also expected that recent developments of siRNA techniques to develop experimental gene therapies for dominantly inherited diseases, or the use of gene transfer into neonatal brains for the treatment of recessive lysosomal disorders such as Batten's disease and others, will be soon entering advanced clinical trials. The fact that this book is not able to cover all possible areas of neurological gene therapy is a recognition of how much the field has grown during the last ten years, as to truly stun anyone who has not followed the field closely during these years.

We expect this book to provide a current illustration of the reviewed fields, and the expectation to leave the reader asking for more, in the hope that future books will have to be dedicated solely to clinical trials in gene therapy for the treatment of neurological disorders.

For those of us in the field, we expect to enroll you readers in the excitement and privilege of further developing the possibility of establishing true molecular medicine as an essential addition to the modern armamentarium of the clinician and surgeon in the 21st century.