Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors

Eric Wickstrom

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000145953
• Topic: Medicine
• Subtopic: Genetics in Medicine

An important new collection of clinical and preclinical reports on genetic therapy, this book describes illustrative examples of diseases in which gene-based interventions are presently plausible, and presents case studies of current research using both synthetic oligonucleotides and biological vectors.
Combining the insights of over 50 contributors, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors

furnishes a historical overview of genetic therapy

highlights official Food and Drug Administration positions on the preparation of oligonucleotides and vectors

offers practical models of agent preparation, animal testing, pharmacokinetics, toxicology, and clinical trials

discusses both synthetic DNA and biological vector approaches to cancer, viral, and cardiological indications

illustrates for new practitioners how each stage of genetic therapy is developed

details genetic treatment of leukemia; lymphoma; cancer of the brain, breast, colon, kidney, and lung; melanoma; HIV; and coronary restenosis

includes examples of antisense, ribozyme, tumor suppressor, immunostimulation, and gene replacement therapy

and addresses questions of preparation, delivery, toxicity, mechanism, and specificity.

1
A Brief History of Genetic Therapy: Gene Therapy, Antisense Technology, and Genomics

James W. Hawkins Antisense and Nucleic Acid Drug Development, Clarksburg, Maryland

I. INTRODUCTION

At first glance, the biology of life appears to offer a complexity beyond comprehension. Hundreds of thousands of different organisms present themselves in diverse physical forms and pursue countless strategies for survival and reproduction. Since its inception, experimental science has sought to devise models that unify our understanding of biology. In turn, modern medicine and therapeutics have increasingly relied on such unifying systems in order to develop technologies to effectively address human disease.

In this century, our appreciation of biology has progressively shifted from one based upon biological structure to one focused on underlying biological function. Anatomy and histology have given way to physiology and cell biology which have spawned biochemistry, leading to molecular biology and, finally, molecular genetics. Although the reader may take pause with such a sweeping conceptualization of the recent history of biology, the direction is unmistakable-the focus of biological thought has made the transition from phenotype to genotype. We now stand in an era where molecular genetics forms the dominant model for biology.

In response to this paradigm shift, our efforts to develop new therapeutics have started to change from those associated with traditional drugs, which address the symptoms of disease, to new genetically based drugs which address the causes of disease. As we proceed into the 21st century, the march toward a comprehensive functional model-a genetic model—of biology will only pick up pace. Likewise, the drive to develop new therapies-genetic therapies-must be expected to remain in step.

The first two branches of genetic therapy to emerge within the new paradigm of biology are gene therapy and antisense technology. This article seeks to briefly introduce these two disciplines to the level necessary to make them understandable and give them a historical context. It further invites the reader to put these technologies into a new integrated frame of genetic reference—the frame of reference of the emerging field of genomics.

In addressing the task of offering a historical treatment of genetic therapy, or perhaps more broadly, genetically targeted research and development, the author has not attempted to set down a rigid historical sequence of events or to attribute the birth of ideas or materials to individuals or groups. Rather, events, concepts, key papers and technologies which have converged to identify a distinct approach to a branch of genetic therapy have been noted. Generally, genetic therapy technologies are treated in detail up to historical events around 1990, a point at which most disciplines had addressed proof of principle with cellular and in vivo experimentation. The discussion of the field after 1990 is presented with more emphasis on emerging clinical development, and the reader is pointed to review articles for the intimate details and progress of basic research in each discipline. In short, this chapter is designed more to offer the beginnings of historical threads to entice the inquisitive reader into any or all of the new fields contributing to genetic therapy rather than to offer historical closure to ideas or career contributions.

This article also seeks to describe the potential interrelationships among gene therapy, antisense technology, and the evolving foundation of molecular genetics on which the future progress and proposed unification of these fields is ultimately based.

II. CLASSICAL GENETICS AND THE HISTORICAL FOUNDATION OF GENETIC THERAPY

II.A. Classical Genetics: Genotype from Phenotype

Many people believe that genetic therapy-the notion of controlling biology or treating disease through genetic mechanisms-is a modern invention. It is not. Early societies recognized genetic forces at work in populations and moved to promulgate social forces against incest; these prohibitions implicitly sought to control deleterious genetic traits resulting from human crosses which could result in nonadaptive homozygous recessive offspring.

Other early efforts at genetic manipulation were empirical, employing phenotype, the physical manifestation of genetic forces, to predict the outcome of genetics. Although crude by today's standards, an understanding of genetics through phenotype proved simple and powerful. The selective breeding of animals and crops, which has taken place worldwide over centuries, is a testament to the potency of the phenotypic approach to genetics.

With the rise of modern science, the practice of genetics moved from an empirical to an experimental discipline. The scientific study of phenotype led to Mendel's laws of heredity which were published in 1866 (Mendel, 1866). However, the field of science did not place emphasis on Mendel's work at the time. While perhaps bewildering to us, the events of this period demonstrate an intellectual struggle to rationalize other established and competing perspectives on biology, none of which were satisfactory, to form a unifying explanation of genetic phenomena (Mayer, 1982).

Beginning in the 1870s, however, technical advances including improved microscopes and new aniline dyes allowed the detailed observation of the cell nucleus; in 1879 Flemming described heavily staining cellular figures, chromatin, which were subsequently termed chromosomes to describe the same structures we know today. In 1883, Weismann concluded that nuclear material was the substance of heredity; in 1889 (Weismann, 1889) he wrote that his theory was,

founded upon the idea that heredity is brought about by the transmission from one generation to another of a substance with a definite chemical and, above all, molecular constitution.

The moment was ripe. The abstract Mendelian notion of an underlying pattern to genetic forces and the concept that the discrete physical material on chromosomes could mediate these forces were united. By 1904, the Sutton-Boveri chromosomal theory of inheritance provided the proof that some chromosomes are individually recognizable during mitosis and meiosis and that chromosomes with the same characteristics occur again and again at each cell divi...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Foreword: Genetic Therapy in the 21st Century
• Preface: From Theory to Practice in Thirty Years
• Contents
• Contributors
• 1. A Brief History of Genetic Therapy: Gene Therapy, Anti-sense Technology, and Genomics
• 2. Preclinical Development of Antisense Oligonucleotide Therapeutics for Cancer: Regulatory Aspects
• 3. Commercial Scale Manufacturing of Oligonucleotides Under Good Manufacturing Practices
• 4. The Regulatory Process and Gene Therapy
• 5. Production of Clinical Lots of Gene Therapy Vectors Using Good Manufacturing Practice: Experience in a University Setting
• 6. Gene Therapy Clinical Trials for Adenosine Deaminase Deficiency/Severe Combined Immunodeficiency
• 7. Development of an Oligodeoxynucleotide Pharmaceutical for the Treatment of Human Leukemia
• 8. Clinical Trials with Anti-p53 DNA, OL(1)p53, in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndrome
• 9. Human Bcl-2 Antisense Therapy for Lymphomas
• 10. Retroviral Gene Transfer in Autologous Bone Marrow and Stem Cell Transplantation
• 11. Adenoviral Gene Transfer of the Herpes Virus Thymidine Kinase Gene for Treating Gliomas
• 12. Distribution and Toxicity of Retroviral Vectors After Intracavitary Delivery in Mouse and Man
• 13. Clinical and Immunologic Responses to Gene Transfer of an Allogeneic Major Histocompatibility Complex Antigen
• 14. Defective Tumor Suppressor Gene Replacement and Oncogene Inactivation for the Treatment of Cancer
• 15. The Molecular Basis of Bladder Cancer and Prospects for Gene Therapy Using Hammerhead Ribozymes
• l6. In Situ Gene Insertion for Immunotherapy Using Vaccinia Virus Vectors
• 17. Antisense Oligonucleotide-Based Therapy for HIV-1 Infection from Laboratory to Clinical Trials
• 18. Treatment of Retinitis Induced by Cytomegalovirus Using Intravitreal Fomivirsen (Isis 2922)
• 19.· Synthetic DNA-Based Compounds for the Prevention of Coronary Restenosis: Current Status and Future Challenges
• 20. Prevention of Restenosis by Gene Targeting
• Index