What More Is There to Ad?
Authors: Matthew D. Weitzman
Journal: Molecular Therapy (2000)

Since their discovery in the 1950s, adenoviruses have provided incredible tools for biologists. Adenovirology continues to be an active field but the greatest contribution that they have made in recent years is in gene delivery. This has in turn spurned greater interest in the basic biology of adenoviruses. Through an understanding of the requirements for replication of the virus came the development of the first replication-defective vectors expressing foreign transgenes. This led to an initial explosion of reports showing in vivo transduction. Then the problems began to surface: The lack of persistence, the immune response, the emergence of replication-competent virus, etc. Those researchers developing adenoviral vectors responded with an array of solutions that attempted to bypass some of these limitations. So-called second- and third-generation versions of the vector contained deletions of genes believed to be responsible for de novo synthesis of viral antigens and were eventually deleted of all viral genes.Adenoviruses are thus an excellent example of how knowledge of the basic biology of a virus was used to generate recombinant vectors for in vivo gene delivery and how further adaptations by creative researchers generated more sophisticated versions to tackle problems as they revealed themselves. This single volume, edited by Prem Seth, covers the basic biology of adenovirus, the development of adenoviral vectors, and the application of those vectors to several gene therapy settings.The book is divided into six sections. The first describes the discovery of adenoviruses and also reviews the structure of the genome and the capsid. This includes a lovely historical introduction from Harold Ginsberg with some personal reflections on the discovery of adenovirus by Wally Rowe. The second section covers steps involved in the virus life cycle, including entry into the host cell, viral gene expression, replication and final assembly of the virion, and packaging of the DNA genome.The development of adenoviral vectors is covered in the third part, along with preclinical evaluation of vectors for gene transfer in various disease settings. This is followed by descriptions of various approaches to modify adenoviruses in order to target infection, integration, or gene expression of adenoviral vectors. Included in this fourth section is an intriguing chapter on the potential use of adenovirus to purge autografts by selective elimination of malignant cells.Some of the safety issues relevant to the use of adenoviral vectors are outlined in the fifth section. Included here are chapters on the potential oncogenicity of adenovirus proteins, the chances for homologous recombination between the virus and the host genome, and three chapters dealing with immune responses. The chapter on homologous recombination gives a very nice historical summary of studies that have detected recombination with integrated adenovirus sequences. This chapter also serves as a good example of how the field tackled some of the inherent problems with developing adenovirus vectors. The fascinating interplay between the host immune system and the elaborate mechanisms developed by adenoviral proteins to counter attack is nicely described.The sixth and final section of the book deals with the current status of ongoing clinical protocols that use recombinant adenoviruses for treatment of cystic fibrosis and cancer. These chapters will be more useful for clinicians who are contemplating their own gene therapy trials with adenovirus vectors. The fact that they all deal with Phase I trials highlights the limited clinical experience with these vectors for human gene therapy to date.On the whole, this book is a cohesive and logically organized introduction to adenoviruses and their applications as vectors for gene therapy. The book is appropriate for graduate students and postdocs interested in the development of recombinant adenovirus vectors, as well as for clinicians who have selected adenovirus as the vector system of choice for a specific disease. The editor should be commended for his efforts to avoid repetition and his attempts to refer to other chapters where appropriate. On the whole, the chapters are very focused (some are only a few pages long).The chapters on the basic biology are well written and are excellent resources for those entering the adenoviral vectors field. Unfortunately the transition chapters are a little weak. There are now many techniques by which one can generate a recombinant adenovirus and researchers who are new to the field would benefit from a full description of each approach with the pros and cons of the different strategies. Although many of these are mentioned, there is not enough discussion to help the uninitiated make their selection. The list of authors shows some glaring omissions of people one would expect had to appear in a line-up of adenovirus gene therapy experts. Some of the chapters are focused almost exclusively on the work in the authors’ own lab. This is particularly true of the section on targeted and hybrid viruses and is somewhat of a shame as this is one of the most promising areas of development in adenovirus vectors and is likely to yield solutions to some of the limitations of the adenovirus system.In short, the book is fairly thorough, if already a bit out of date (in many chapters the most recent references are from 1997). This problem is unavoidable in any rapidly changing area of biomedical research. In addition, it would have been useful to include a methods chapter with detailed protocols, so that having grasped the basic biology, readers then had a manual that also allowed them to move toward a gene therapy application.Perhaps an even more pertinent question is, what more will there be to Ad? Most chapters in the book end with a conclusion and a few thoughts on the future prospects for research and therapy. Given the recent tragic death of a patient receiving an adenovirus vector and the subsequent scrutiny of gene therapy clinical trials, it is necessary to ask what future adenovirus vectors will have in gene therapy. Although they may not be well suited to protein replacement therapy in genetic diseases, adenovirus vectors are likely to have a role in cancer therapies. If there is a move away from the use of adenovirus vectors, then this book may serve as an historical benchmark of where we were at the beginning of the new millennium. However, if adenoviruses continue to be used in gene therapy, it is clear that we need to increase our understanding of the basic biology and the interactions between adenoviruses and their hosts. Only through these fundamental studies will we be able to develop improved vectors for gene therapy. Since their discovery in the 1950s, adenoviruses have provided incredible tools for biologists. Adenovirology continues to be an active field but the greatest contribution that they have made in recent years is in gene delivery. This has in turn spurned greater interest in the basic biology of adenoviruses. Through an understanding of the requirements for replication of the virus came the development of the first replication-defective vectors expressing foreign transgenes. This led to an initial explosion of reports showing in vivo transduction. Then the problems began to surface: The lack of persistence, the immune response, the emergence of replication-competent virus, etc. Those researchers developing adenoviral vectors responded with an array of solutions that attempted to bypass some of these limitations. So-called second- and third-generation versions of the vector contained deletions of genes believed to be responsible for de novo synthesis of viral antigens and were eventually deleted of all viral genes. Adenoviruses are thus an excellent example of how knowledge of the basic biology of a virus was used to generate recombinant vectors for in vivo gene delivery and how further adaptations by creative researchers generated more sophisticated versions to tackle problems as they revealed themselves. This single volume, edited by Prem Seth, covers the basic biology of adenovirus, the development of adenoviral vectors, and the application of those vectors to several gene therapy settings. The book is divided into six sections. The first describes the discovery of adenoviruses and also reviews the structure of the genome and the capsid. This includes a lovely historical introduction from Harold Ginsberg with some personal reflections on the discovery of adenovirus by Wally Rowe. The second section covers steps involved in the virus life cycle, including entry into the host cell, viral gene expression, replication and final assembly of the virion, and packaging of the DNA genome. The development of adenoviral vectors is covered in the third part, along with preclinical evaluation of vectors for gene transfer in various disease settings. This is followed by descriptions of various approaches to modify adenoviruses in order to target infection, integration, or gene expression of adenoviral vectors. Included in this fourth section is an intriguing chapter on the potential use of adenovirus to purge autografts by selective elimination of malignant cells. Some of the safety issues relevant to the use of adenoviral vectors are outlined in the fifth section. Included here are chapters on the potential oncogenicity of adenovirus proteins, the chances for homologous recombination between the virus and the host genome, and three chapters dealing with immune responses. The chapter on homologous recombination gives a very nice historical summary of studies that have detected recombination with integrated adenovirus sequences. This chapter also serves as a good example of how the field tackled some of the inherent problems with developing adenovirus vectors. The fascinating interplay between the host immune system and the elaborate mechanisms developed by adenoviral proteins to counter attack is nicely described. The sixth and final section of the book deals with the current status of ongoing clinical protocols that use recombinant adenoviruses for treatment of cystic fibrosis and cancer. These chapters will be more useful for clinicians who are contemplating their own gene therapy trials with adenovirus vectors. The fact that they all deal with Phase I trials highlights the limited clinical experience with these vectors for human gene therapy to date. On the whole, this book is a cohesive and logically organized introduction to adenoviruses and their applications as vectors for gene therapy. The book is appropriate for graduate students and postdocs interested in the development of recombinant adenovirus vectors, as well as for clinicians who have selected adenovirus as the vector system of choice for a specific disease. The editor should be commended for his efforts to avoid repetition and his attempts to refer to other chapters where appropriate. On the whole, the chapters are very focused (some are only a few pages long). The chapters on the basic biology are well written and are excellent resources for those entering the adenoviral vectors field. Unfortunately the transition chapters are a little weak. There are now many techniques by which one can generate a recombinant adenovirus and researchers who are new to the field would benefit from a full description of each approach with the pros and cons of the different strategies. Although many of these are mentioned, there is not enough discussion to help the uninitiated make their selection. The list of authors shows some glaring omissions of people one would expect had to appear in a line-up of adenovirus gene therapy experts. Some of the chapters are focused almost exclusively on the work in the authors’ own lab. This is particularly true of the section on targeted and hybrid viruses and is somewhat of a shame as this is one of the most promising areas of development in adenovirus vectors and is likely to yield solutions to some of the limitations of the adenovirus system. In short, the book is fairly thorough, if already a bit out of date (in many chapters the most recent references are from 1997). This problem is unavoidable in any rapidly changing area of biomedical research. In addition, it would have been useful to include a methods chapter with detailed protocols, so that having grasped the basic biology, readers then had a manual that also allowed them to move toward a gene therapy application. Perhaps an even more pertinent question is, what more will there be to Ad? Most chapters in the book end with a conclusion and a few thoughts on the future prospects for research and therapy. Given the recent tragic death of a patient receiving an adenovirus vector and the subsequent scrutiny of gene therapy clinical trials, it is necessary to ask what future adenovirus vectors will have in gene therapy. Although they may not be well suited to protein replacement therapy in genetic diseases, adenovirus vectors are likely to have a role in cancer therapies. If there is a move away from the use of adenovirus vectors, then this book may serve as an historical benchmark of where we were at the beginning of the new millennium. However, if adenoviruses continue to be used in gene therapy, it is clear that we need to increase our understanding of the basic biology and the interactions between adenoviruses and their hosts. Only through these fundamental studies will we be able to develop improved vectors for gene therapy.