Abstract

Gene Therapy: Principles and Application (T. Blankenstein (ed.) Birkhäuser Verlag, Basel-Boston-Berlin, 1999)

This book gives a modern description of one of the most intensively developing branches of medico-biological sciences, gene therapy.

The first part of this book considers methods of genetic material delivery suitable for in vivo application. Chapters 1 (written by P. Robbins), 2 (by G. Wolff), and 5 (by M. Hallek, C.-M. Wendtner, R. Kotin, D. Michl, and E.-L. Winnacker) deal with the most effective methods of gene delivery using recombinant viruses. Chapter 1 describes the basic principles of construction and use of retroviral vectors that are commonly employed for trials of gene therapy methods. It contains information on the life cycle and composition of their genome. Attention is given to the description of types of retroviral vectors used for transfection, long terminal repeats (LTR) involved in viral integration into the host genome, and packing lines used for vector construction.

Chapter 2 considers adenoviral vectors as tools for gene delivery. It also contains information about the composition of adenoviruses and principles of construction of recombinant adenoviral vectors. In contrast to retroviral vectors, genetic material introduced into the target cell by adenoviral vectors is located in cellular episomes. Although recombinant adenovirus delivery systems operate very effectively, they are highly immunogenic, and this results in a rapid decrease in the expression of the transferred gene. Excision of certain parts of the adenoviral genome reduces immunogenicity of adenoviral vectors. Adenoviruses replicating only in protein p53 deficient mutant cells have been specially developed for gene therapy of cancer.

Chapter 5 describes advantages of the use of small DNA-containing adeno-associated viruses for gene transfer. These viruses can transfer genes into terminally differentiated cells. They are characterized by lack of pathogenicity, low immunogenicity, relative stability of the transferred gene, and potential ability for directed integration of genetic material.

Chapter 3 (written by E. Wagner) introduces the advantages of non-viral gene delivery: the possibility of use of large size DNA, relatively cheap plasmid DNA and synthetic reagents for transfection, easy testing of the recombinant material safety, etc. Many ligands unique for certain cells types (asialoglycoproteins for hepatocytes, anti-CD-3 for T-lymphocytes) or characterized by wide specificity (insulin, transferrin) have been used for a very promising approach in gene therapy, receptor-mediated gene transfer. This approach requires the presence of a specific ligand attached to DNA by a polycation providing a compact package of DNA and its protection. Numerous methods developed for receptor-mediated gene delivery also employ additional components for intracellular transport (responsible for release from endosomes and transport into the nucleus).

Chapter 4 (written by O. Bagasra, M. Amjaid, and M. Muchtar) describes methods that use liposomes for gene delivery. It includes the description of preparation of various types of liposomes for DNA delivery: cationic, anionic, pH-sensitive, immunoliposomes. This chapter also considers further perspectives of the liposomal method: use of lipopolyamines and insertion of ligands providing receptor-mediated endocytosis. The first part of this book ends with a chapter (written by H. Tahara, T. Kitagawa, T. Iwazawa, and M. Lotze), describing gene transfer by a particle-mediated gun.

The second part of this book considers gene therapy of diseases caused by deficits of single genes. The first chapter of this section (by A. Aiuti and C. Bordignon) deals with approaches for the treatment of dangerous combined immune deficits. This is a group of diseases caused by various factors: defects of lymphocyte receptors, transcriptional factors, enzymes of purine metabolism, etc. Although the effectiveness of gene transfer into stem cells of the immune system is not yet perfected, retroviral vectors have already been employed in clinical practice for correction of such diseases. The second chapter of this section (by J. Barranger and M. Vallor) describes the development and study of experimental models for investigation and correction of lysosomal diseases (caused by deficit of some lysosomal enzymes); with this approach, it is possible to investigate such diseases and ways of their treatment without clinical experimentation.

The third chapter of this section (written by D. Porteous and J. Innes) deals with gene therapy of the dangerous monogenic disease cystic fibrosis. The authors discuss detection of the efficacy of transmembrane conductivity regulator gene transfer with point mutations, various methods of gene transfer for the treatment of this disease, and ways for vector delivery to lung epithelium. They believe that the development of effective and safe delivery methods will allow the treatment of this disease by gene therapy of somatic cells.

The last chapter of this section (by G. Cichon and M. Strauss) is devoted to gene therapy of familial hypercholesterolemia. This is one of the most widespread dominant hereditary diseases caused by a defect in the low density lipoprotein receptor. The authors describe reasons and clinical manifestations, experiments on model animals, and the first clinical trials of gene therapy for this disease.

Gene transfer into somatic or malignant cells for the investigation of their subsequent fate is a branch that shares methods and goals with gene therapy. Such approach suitable for determination of optimal strategy of treatment, say malignant tumors, can be called genetic marking. The aminoglycoside transferase gene responsible for tolerance to the antibiotic G-418 is used for this purpose most frequently. The use of this method during autologic transplantation of bone marrow and peripheral blood cells for the treatment of hematological and solid tumors opens the third part of the book. (This chapter was written by K. Cornetta, E. Srour, and C. Traycoff). The second chapter (by C. Bonini and C. Bordignon) considers genetic marking of T-lymphocytes. The last chapter of this section (by T. Licht, M. Gottesman, and I. Pastan) deals with the transfer of multiple resistance genes into hematopoietic cells. In this case, the transferred gene is used not only as a marker, but also for in vivo selection of transfected cells. This represents one approach for preventing the reduction of the percentage of cells with the transferred gene for gene therapy.

A large section of the book was reserved for consideration of gene therapy of cancer. This type of treatment usually requires delivery of genetic material into each malignant cell. The first chapter of this section (by A. Gewirtz) describes the use of c-myb protooncogene as a target for anti-sense therapy of leukemia and melanoma.

The transfer of the herpes virus thymidine kinase gene under control of a promoter specific for the tumor cell followed by the addition of acyclovir or its analogs can cause transfected cell death (see chapter 2 by R. Vile). Special attention was given to consideration of the appearance (during viral thymidine kinase application) and practical use of the “spectator effect” causing death of cells neighboring the transfected ones. This chapter also considers systemic effects during in vivo use of this enzyme (e.g., immune and vascular effects). Problem of tumor immunogenicity and ways for its increase are considered in the next chapter (by F. Cavallo, P. Nanni, P. Dellabona, P. Lollini, G. Gasorati, and G. Forni).

Chapter 4 of this section (S. Cayeux, Z. Qin, B. Dörken, and T. Blankenstein) considers problem in the use of transfected tumor cells for the development of antitumor vaccines. Genes encoding various cytokines (e.g., interleukins, tumor necrosis factor, gamma-interferon) are promising for the development of such vaccines. Chapter 8 (by X. Cao) contains information on the combined effect of chemotherapy and antitumor cellular vaccines obtained using gene transfer. Chapter 5 (by E. Nöbler and D. Schendel) describes the interaction of T-cell immunity and tumor and also the development of autologic and allogenic antitumor cell vaccines. The next chapter (written by Th. Wölfel) considers the problem of identification of tumor antigen epitopes; being displayed by antigen-presenting cells, they cause immune response against the tumor cells. The use of peptides sequences corresponding to that of the epitopes for immune therapy of malignant tumors was described in this chapter and also in chapter 7 (written by R. Toes, F. Ossendorp, E. van der Voort, E. Mengede, R. Offringa, and C. Melief).

The book not only reflects the current state of modern methods used in gene therapy, but it also describes prospects for their use in clinical practice.

A. A. Rozenkranz