Gene Therapy for Neurological Disorders and Brain Tumors

458 Pages·1998·11.864 MB·English

by  Steven A. Reeves (auth.), E. Antonio Chiocca MD, PhD, Xandra O. Breakefield PhD (eds.)

Gene Therapy for Neurological Disorders
and Brain Tumors
Contemporary Neuroscience
Gene Therapy for Neurological Disorders and Brain Tumors, edited by E. Antonio
Chiocca and Xandra 0. Breakefield, 1998
Highly Selective Neurotoxins: Basic and Clinical Applications, edited by Richard M.
Kostrzewa, 1998
Neuroinjlammation: Mechanisms and Management, edited by PaulL. Wood, 1998
Neuroprotective Signal Transduction, edited by Mark P. Mattson, 1998
Clinical Pharmacology of Cerebral Ischemia, edited by Gert J. TerHorst
and Jakob Korf, 1997
Molecular Mechanisms of Dementia, edited by Wilma Wasco and
Rudolph E. Tanzi, 1997
Neurotransmitter Transporters: Structure, Function, and Regulation,
edited by Maarten E. A. Reith, 1997
Motor Activity and Movement Disorders: Research Issues and Applications,
edited by Paul R. Sanberg, Klaus-Peter Ossenkopp, and Martin
Kavaliers, 1996
Neurotherapeutics: Emerging Strategies, edited by Linda M. Pullan
and Jitendra Patel, 1996
Neuron-Glia Interrelations During Phylogeny: II. Plasticity
and Regeneration, edited by Antonia Vernadakis
and Betty I. Roots, 1995
Neuron-Glia Interrelations During Phylogeny: I. Phylogeny
and Ontogeny of Glial Cells, edited by Antonia Vernadakis
and Betty I. Roots, 199 5
The Biology of Neuropeptide Y and Related Pep tides, edited
by William F. Colmers and Claes Wahlestedt, 1993
Psychoactive Drugs: Tolerance and Sensitization, edited
by A. J. Goudie and M. W. Emmett-Oglesby, 1989
Experimental Psychopharmacology, edited by Andrew J. Greenshaw
and Colin T. Dourish, 1987
Developmental Neurobiology of the Autonomic Nervous System, edited
by Phyllis M. Gootman, 1986
The Auditory Midbrain, edited by Lindsay Aitkin, 1985
Neurobiology of the Trace Elements, edited by Ivor E. Dreosti
and Richard M. Smith
Vol. 1: Trace Element Neurobiology and Deficiencies, 1983
Vol. 2: Neurotoxicology and Neuropharmacology, 1983
Gene Therapy
for Neurological
Disorders
and
Brain Tumors
Edited by
E. Antonio Chiocca, MD, PhD
Massachusetts General Hospital and Harvard Medical School
Boston, MA
Xandra 0. Breakefield, PhD
Massachusetts General Hospital and Harvard Medical School
Boston, MA
Springer Science+Business Media, LLC
ISBN 978-1-4757-5314-1 ISBN 978-1-59259-478-8 (eBook)
DOI 10.1007/978-1-59259-478-8
© 1998 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1998
Softcover reprint of the hardcover 1st edition 1998
All rights reserved.
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the
Publisher.
All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not
necessarily reflect the views of the publisher.
This publication is printed on acid-free paper. Q
ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials.
Cover illustration: (Left to right) Fig. 2 from "Current Treatment Modalities for Brain Tumor: Surgery, Radiation, and
Chemotherapy," by Stephen B. Tatter and Griffith R. Harsh IV; Fig. 3 from "Retrovirus Vectors and Regulatable
Promoters," by Steven A. Reeves; Fig. 9 from "Tumor Suppressor Gene Therapy for Brain Tumors," by Candelaria
Gomez-Manzano, Juan Fueyo, Athanassios P. Kyritsis, and W. K. Alfred Yung.
Cover design by Patricia F. Cleary.
Photocopy Authorization Policy:
Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted
by Springer Science+B usiness Media, LLC.,
provided that the base fee of US $8.00 per copy, plus US $00.25 per page, is paid directly to the
Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been
granted a photocopy license from the CCC, a separate system ofp ayment has been arranged and is acceptable to
Springer Science+B usiness Media, LLC.
The fee code for users of the Transactional Reporting Service is: [0-89603-507-7/97 $8.00 + $00.25].
Preface
As knowledge about the molecular events responsible for the delivery and expres
sion of genes into cells accumulates, we are beginning to contemplate how to perma
nently alter the cellular genome in order to affect diseases of the central nervous system.
The theoretical possibilities of "gene therapy" are immense, yet their reduction into a
clinical practice remains the object of intense investigations.
The ingredients of this discipline are: 1) the intracellular method of delivery and
expression of the gene (the vector), 2) the therapeutic gene (the transgene), and 3) the
inoculation route for the vector/transgene.
Vectors are based on genetically-modified viruses, genetically-engineered cells, or
artificial lipid/protein formulations (liposomes or virosomes). Numerous viral vectors
appear suitable for delivery of a therapeutic gene into tumor or endogenous neural cells
(neurons, glia, and endothelial cells). For some anticancer applications, replication
conditional viruses (adenoviruses or herpes viruses) may provide the most benefit. On
the contrary, lentiviral vectors, AAV vectors, or helper-free herpes amplicons may be
more suitable for delivery of trans genes into neurons.
Appropriate therapeutic genes can be employed to produce an antiproliferative ef
fect. This would be most useful to treat neoplasms or to inhibit stenosis (and possibly
vasospasm) of cerebral blood vessels. Other transgenes can be used to produce
neuroprotective effects. For example, intraneuronal delivery and expression of genes
encoding appropriate growth factors, growth factor receptors, or anti-apoptotic genes
may provide potential treatments for ischemic disorders, neurodegenerative disorders,
epilepsy, traumatic injuries, and painful neurogenic syndromes. Inherited disorders of
metabolism that affect the nervous system are also appropriate targets for gene therapy.
Even more novel technologies that employ antisense nucleotides, ribozyme molecules,
tRNA suppressor genes, or nucleic acid decoys allow selective targeting of gene tran
scription and mRNA translation. This can now provide a means to affect the neuronal
phenotype of autosomal dominant disorders such as Huntington's disease.
As these technologies are being developed, neurologic, neuroradiologic, and
neurosurgical expertise and experience are required to determine which vector and
which transgene are most suitable for a particular disease. In particular, the route of
delivery of a gene therapy is a relevant variable that needs the intervention of the clini
cian. For example, it is likely that multiple vector, transgene, and delivery routes will
be needed to successfully treat the margin of a freshly resected glioblastoma, to inhibit
glioblastoma cells from migrating and proliferating, and to prevent the recurrence of a
distant secondary tumor. On the other hand, the catheters of the neurovascular inter
ventionist can deliver one vector/transgene into a selected cerebral blood vessel to pre
vent future stenosis, restenosis, or vasospasm. Lastly, stereotactic inoculations into the
v
vi Preface
substantia nigra/globus pallidus or into the hippocampus may be sufficient for delivery
of appropriate vectors/ trans genes needed to treat Parkinson's disease or temporal lobe
epilepsy, respectively. The interaction between the gene therapist and the neurologic
clinician will provide an enormous impetus to current efforts aimed at reducing gene
therapy models into a feasible clinical practice.
The feasibility of gene therapy is being studied through clinical trials. The desperate
plight of patients suffering from malignant gliomas has driven us to attempt safety and
efficacy studies of anticancer gene therapy. It is likely that results form these trials will
provide two main findings: 1) Safety of genetically-altered viral vectors will be estab
lished. This will then permit the use of these vectors as delivery agents for therapeutic
genes aimed at less malignant tumors or aimed at disorders of the nervous system
(ischemia, trauma, neurodegenerative disorders), 2) Glioblastoma regression will be
marginal at best. If the conduct of the clinical trial is designed to maximize the amount
of scientific information that can be derived, attempts to improve or modify the vector/
transgene/delivery variables will be possible. It is likely that combinations of these
agents will have to be designed in order to target molecularly heterogeneous
glioblastoma cells spread throughout the brain.
In spite of the wealth ofknowledge and ideas, multiple problems remain to be solved.
Transgenes and their vectors produce an immune response that limits the extent and
duration of gene expression. This problem is most evident with adenovirus vectors and
least evident with the artificial vector systems. The intracellular level and persistence
of trans gene expression is also a limitation of current technologies, although progress
in achieving stable expression with hybrid herpes/ EBV amplicons or with integrating
vectors based on lentivirus or AA V may soon overcome this. Furthermore, incorpora
tion ofhypomethylating gene elements may provide a means to inhibit promoter shut
off. Of course, possible short- and long-term neurotoxic effects from some of the
employed vectors, such as lentivirus or herpes virus, remains a constant concern.
In conclusion, the unrealistic perception of gene therapy as a "cure" or as "a failed
treatment", created by premature and exaggerated news reports, is likely to disappear
as current problems in the application to clinical practice become solved. The amount
of money spent by the NIH on gene therapy technology is increasing. Every pharma
ceutical company possesses either a gene therapy branch or is associated with a bio
technology venture that is pursuing it. The number of clinicians and scientists interested
in gene therapy is increasing. Annual meetings of multiple scientific and clinical disci
plines have entire sessions dedicated to this field. It is our hope that the magnitude of
this endeavor will result in a successful therapeutic outcome. It is also exciting that this
field is permitting us to translate molecular knowledge about genes and cells into a
therapeutic benefit for the patient.
E. Antonio Chiocca
Xandra 0. Breakejield
Contents
Preface ................................................................................................................... v
List of Contributors ............................................................................................ ix
PART I. VECTORS AND PROMOTERS
Vectors for Gene Delivery to the Central Nervous System:
An Overview
Joseph Glorioso ................................................................................................... 3
1 Retrovirus Vectors and Regulatable Promoters
Steven A. Reeves .................................................................................................. 7
2 Characteristics of Adenovirus Vectors
Susanna Chiocca and Matt Cotten ............................................................... 39
3 HSV Recombinant Vectors: General Characteristics and Potential
for Use in the Central Nervous System
Paul A. Johnson ................................................................................................. 53
4 HSV -1 Amplicon
Cornel Fraefel, Xandra 0. Breakefield, and David R. Jacoby .................. 63
5 AA V Vectors: General Characteristics and Potential
for Use in the Central Nervous System
Frances I. Smith and Thomas J. McCown .................................................... 83
6 EBV Vectors: General Characteristics and Potential for Gene Therapy
in the Central Nervous System
Jean-Michel H. Vos, Keith B. Quattrocchi,
and Brian J. Wendelburg .............................................................................. 93
7 Lentiviral Vectors for Gene Delivery in the Central Nervous System
Didier Trono, Ulrike Blomer, and Luigi Naldini ...................................... 113
8 Promoters for Expression of Gene Products Within Neurons and Glia
John W. Henson ............................................................................................... 121
9 Immune Response to Viral Vectors
Jason G. Smith and Stephen L. Eck .............................................................. 147
PART II. NEURO-ONCOLOGY
10 Current Treatment Modalities for Brain Tumor: Surgery, Radiation,
and Chemotherapy
Stephen B. Tatter and Griffith R. Harsh IV ............................................... 161
vii
Vlll Contents
11 Experimental and Clinical Gene Therapies for Brain Tumors
E. Antonio Chiocca ......................................................................................... 191
12 Tumor Suppressor Gene Therapy for Brain Tumors
Candelaria Gomez-Manzano, Juan Fueyo,
Athanassios P. Kyritsis, and W. K. Alfred Yung .................................. 205
13 Cytokine-Based Gene Therapy for Brain Tumors
John H. Sampson, Darell D. Bigner, and Glen Dranoff ........................... 231
14 Delivery of Therapeutic Genes to Brain and Intracerebral Tumors
Leslie L. Muldoon, Robert A. Kroll, Michael A. Pagel,
Simon Roman-Goldstein, and Edward A. Neuwelt ............................. 295
15 Rat Brain Tumor Models and Statistical Evaluation of Survival Data
in Experimental Neuro-Oncology
Rolf F. Barth and Melvin L. Moeschberger ................................................ 313
PART III. NEUROLOGICAL DISORDERS
Neurological Disorders: An Overview
Anne B. Young .................................................................................................. 341
16 Gene Transfer for Adult CNS Regeneration and Aging
M. C. Senut, I. Aubert, P. J. Horner, and Fred H. Gage ............................ 345
17 Gene Therapy for Parkinson's Disease
Martha C. Bohn and DerekL. Choi-Lundberg ............................................ 3 77
18 Gene Therapy for Ischemic Stroke
Peter A. Feehan, Masazumi Fujii, Cornell Fraefel,
Andreas Jacobs, and Michael A. Moskowitz ....................................... 397
19 Gene Therapy for the Lysomal Storage Diseases
Edward M. Kaye .............................................................................................. 409
20 Gene Therapy for Pain
Gudarz Davar .................................................................................................. 419
21 Gene Therapy of Huntington's Disease
Ole Isaeson and Nadia Haque ...................................................................... 427
Index .................................................................................................................. 445
Contributors
I. AuBERT, The Salk Institute for Biological Studies, Laboratory Genetics, La Jolla, CA
RoLF F. BARTH, Department of Pathology, Duke University Medical Center,
Durham,NC
DARELL D. BIGNER, Department of Pathology, Duke University Medical Center,
Durham,NC
ULRIKE BL6MER, The Salk Institute for Biological Studies, La Jolla, CA
MARTHA C. BoHN, Department of Neurobiology and Anatomy, Rochester School of
Medicine and Dentistry, Rochester, NY and Children's Memorial Institute for
Education and Research, Northwestern University School of Medicine, Chicago, IL
XANDRA 0. BREAKEFIELD, Neurogenetics Unit, Massachussetts General Hospital,
Harvard Medical Center, Boston, MA
E. ANTONIO CHIOCCA, Molecular Neuro-Oncology, Neurosurgical Service,
Massachussetts General Hospital, Harvard Medical School Boston, MA
SusANNA CHIOCCA, European Institute of Oncology, Department of Experimental
Oncology, Milan, Italy
DEREK L. CHOI-LUNDBERG, Department of Neurobiology and Anatomy, University of
Rochester School of Medicine and Dentistry, Rochester, NY and Children's
Memorial Institute for Education and Research, Northwestern University School of
Medicine, Chicago, IL
MATT CoTTEN, Institute for Molecular Pathology, Vienna, Austria
GuoARZ DAVAR, Molecular Neurobiology of Pain Laboratory, Anesthesia Ressearch,
Brigham and Women's Hospital, Boston, MA
GLEN DRANOFF, Gene Therapy Laboratories, Dana-Farber Cancer Institute,
Boston,MA
STEVEN L. EcK, Division of Hematology/Oncology, Department of Medicine,
University of Pennsylvania, Philadelphia, PA
CoRNEL FRAEFEL, Neurogenetics Unit, Massachussetts General Hospital, Harvard
Medical School, Boston, MA
JuAN FuEYO, Department ofNeuro-Oncology, Brain Tumor Center, University of
Texas M.D. Anderson Cancer Center, Houston, TX
MASAZUMI FUJII, Stroke and Neurovascular Regulation Research Laboratory,
Departments of Neurology and Neurosurgery, Massachussetts General Hospital,
Charlestown MA and Department of Neurosurgery, Nagoya University School of
Medicine, Nagoay, Japan
FRED H. GAGE, The Salk Institute for Biological Studies, La Jolla, CA
ix