Safe, efficient, and specific delivery of therapeutic genes remains an important bottleneck for the development of gene therapy. Synthetic, nonviral systems have a unique pharmaceutical profile with potential advantages for certain applications. Targeting of the synthetic vector improves the specificity of gene medicines through a modulation of the carriers' biodistribution, thus creating a dose differential between healthy tissue and the target site. The biodistribution of current carrier systems is being influenced to a large extent by intrinsic physicochemical characteristics, such as charge and size. Consequently, such nonspecific interactions can interfere with specific targeting, for example, by ligands. Therefore, a
carrier complex should ideally be inert, that is, free from intrinsic properties that would bias its distribution away from the target site. Strategies such as coating of DNA carrier complexes with hydrophilic polymers have been used to mask some of these intrinsic targeting effects and avoid nonspecific interactions. Preexisting endogenous ligand-receptor interactions
have frequently been used for targeting to certain cell types or tumours. Recently exogenous ligands have been derived from microorganisms or, like antibodies or phage-derived peptides,
developed de novo. In animal models, such synthetic vectors have targeted remote sites such as a tumour. Furthermore, the therapeutic proof of the concept has been demonstrated for
fitting combinations of synthetic vectors and therapeutic gene.

Andreas G. Sch&#228;tzlein

Targeting of Synthetic Gene Delivery Systems

Current curative strategies for prostate cancer are restricted to the primary tumour, and the effect of treatments to control metastatic disease is not sustained. Therefore, the application of gene therapy to prostate cancer is an attractive alternative. Baculoviruses are highly restricted insect viruses, which can enter, but not replicate in mammalian cells. Baculoviruses can incorporate large amounts of extra genetic material, and will express transgenes in mammalian cells when under the control of a mammalian or strong viral promoter. Successful gene delivery has been achieved both in vitro and in vivo and into both dividing and nondividing cells, which is important since prostate cancers divide relatively slowly. In addition, the envelope protein gp64 is sufficiently mutable to allow targeted transduction of particular cell types. In this review, the advantages of using baculoviruses for prostate cancer gene therapy are explored, and the mechanisms of viral entry and transgene expression are described.

Lindsay J. Stanbridge

Vincent  Dussupt

Norman J. Maitland

Baculoviruses as Vectors for Gene Therapy against Human Prostate Cancer

Gene therapy is reaching a stage where some clinical benefits have been demonstrated on patients involved in phase I/II clinical trials. However, in many cases, the clinical benefit is hardly measurable and progress in the improvement of gene therapy
formulations is hampered by the lack of objective clinical endpoints to measure transgene delivery and to quantitate transgene expression. However, these endpoints rely almost exclusively on the analysis of biopsies by molecular and histopathological methods. These methods provide only a limited picture of the situation. Therefore, there is a need for a technology that would allow precise, spacio-temporal measurement of gene expression on a whole body scale upon administration of the gene delivery vector. In the field of gene therapy, a considerable effort is being invested in the development of noninvasive imaging of gene expression and this review presents the various strategies currently being developed.

Georges Vassaux

Thomas Groot-Wassink

In Vivo Noninvasive Imaging for Gene Therapy

Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to
tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities
associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following
systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near
future.

Tracy  Robson

David G. Hirst

Transcriptional Targeting in Cancer Gene Therapy

Targeted radionuclide therapy is an alternative method of radiation treatment which uses a tumor-seeking agent carrying a radioactive atom to deposits of tumor, wherever in the body they may be located. Recent experimental data signifies promise for the amalgamation of gene transfer with radionuclide targeting. This review encompasses aspects of the integration of gene
manipulation and targeted radiotherapy, highlighting the possibilities of gene transfer to assist the targeting of cancer with low molecular weight radiopharmaceuticals.

R. J. Mairs

M.  Boyd

Targeting Radiotherapy to Cancer by Gene Transfer

The last decade has seen substantial advances in the development of gene therapy strategies and vector technology for the treatment of a diverse number of diseases, with a view to translating the successes observed in animal models into the clinic. Perhaps the overwhelming drive for the increase in vascular gene transfer studies is the current lack of successful long-term pharmacological treatments for complex cardiovascular diseases. The increase in cardiovascular disease to epidemic proportions has also led many to conclude that drug therapy may have reached a plateau in its efficacy and that gene therapy may represent a realistic solution to a long-term problem. Here, we discuss gene delivery approaches and target diseases.

Kate L. Dishart

Lorraine M. Work

Laura  Denby

Andrew H. Baker

Gene Therapy for Cardiovascular Disease

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