Results of retroviral and adenoviral approaches to cancer gene therapy (original) (raw)
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Adenoviral vectors—How to use them in cancer gene therapy?
Virus Research, 2006
Gene therapy is most often described as a technique for introducing the foreign genetic material into cells with a correction of a dysfunctional gene as its final goal. Today, it is well known that cancer is one of the leading causes of mortality in the world. Besides classical methods for cancer treatment new strategies against cancer are needed. Although originally being designed as a treatment for monogenetic illness, soon after, gene therapy appeared as a potential new strategy in cancer therapy. One of the widely used vectors for cancer gene therapy is adenovirus. In this review we have described molecular biology of adenoviruses and basis for construction of adenoviral vectors. We have also described concepts for cancer gene therapy including their in vitro and in vivo application. Special attention is drawn toward retargeting of adenovirus as a new approach in vector design for cancer gene therapy, in order to restrict transgene expression in tumor tissue. This approach uses biophysical as well as genetic characteristics of tumor itself and its supporting tissue, allowing new "bypass" in cancer gene therapy.
Human Gene Therapy, 2019
After discovery and characterization of the adenovirus in the 1950s, this prevalent cause of the common cold and other usually mild diseases has been modified and utilized in biomedicine in several ways. To date, adenoviruses are the most frequently used vectors and therapeutic (e.g. oncolytic) agents with a number of beneficial features. They infect both dividing and non-dividing cells, enable high-level, transient protein expression, and are easy to amplify to high concentrations. As an important and versatile research tool, it is of essence to understand the limits and advantages that genetic modification of adenovirus vectors may entail. Therefore, we performed a retrospective analysis of adenoviral gene therapy constructs produced in the same laboratory with similar methods. The aim was to assess the impact of various modifications on the physical and functional titer of the virus. We found that, genome size (designed within "the 105% golden rule"), did not significantly affect the physical titer of the adenovirus preparations, regardless of the type of transgene (e.g. immunostimulatory vs other), number of engineered changes, and size of the mutated virus genome. One statistically significant exception was noted, however. Chimeric adenoviruses (5/3) had a slightly lower physical titer compared to Ad5-based viruses, although a trend for the opposite was true for functional titer. Thus, 5/3 chimeric viruses may in fact be appealing from the safety versus efficacy viewpoint. Armed viruses had lower, both functional and physical, titers than unarmed viruses, while five genomic modifications started to decrease functional titer. Importantly, even highly modified armed viruses generally had good titers compatible with clinical testing. In summary, this paper shows the plasticity of adenovirus for various vector, oncolytic, and armed oncolytic uses. These results inform future generations of adenovirus-based drugs for human use. This information is directly transferable to academic laboratories and the biomedical industry involved in vector design and production optimization.
Targeted Adenoviral Vectors for Cancer Gene Therapy
Advances in Experimental Medicine and Biology, 1998
In order to realise the full potential of gene therapy as a rational approach to the treatment of cancer, it will be necessary to achieve delivery of the therapeutic gene selectively to target tumour cells. Such cancer cell-specific gene delivery is mandated in the context of locoregional or compartmentalised carcinomas, and is also an absolute requirement for the treatment of disseminated disease. Moreover, underlying any cancer gene therapy approach is the need to achieve a high level of efficiency of gene transfer to the target cells. Of the existing viral and nonviral gene delivery vehicles, the adeno viral vector uniquely fulfils two requirements of an intra venously administered vector for cancer gene therapy: systemic stability and the ability to accomplish efficient transduction of cancer cells. However, it is necessary to modify native adenoviral tropism in order to achieve selective transduction of target tumour cells. A number of strategies have been developed for this purpose, involving genetic or immunological modifications to either of two adenoviral capsid proteins, the fibre and penton base. These strategies are designed to generate a targetable, injectable vector which would represent a major advance in the field of cancer gene therapy. Contents 1. Introduction: cancer gene therapy 2. Vector requirements for cancer gene therapy 3. The adenovirus is the most promising vector for direct in vivo gene delivery 4. The biology of adenoviral infection 5. The generation of targeted adenoviral vectors by immuno logical modifications of the fibre protein 6. The generation of targeted adenoviral vectors by genetic modifications of the fibre protein 7. The generation of targeted adenoviral vectors by modifications of the penton base 8. Future directions
Modified adenoviruses for cancer gene therapy
International journal of cancer. Journal international du cancer, 2004
Adenoviral gene therapy is an exciting novel approach for treating cancers resistant to currently available therapies. However, currently there is little evidence supporting significant clinical benefits with replication-incompetent adenoviruses. Recent data suggest that expression of the primary receptor, the coxsackie-adenovirus receptor (CAR), may be highly variable on tumor cells, resulting in resistance to infection. Consequently, various strategies have been evaluated to modify adenovirus tropism in order to circumvent CAR deficiency, including retargeting complexes or genetic capsid modifications. To improve tumor penetration and local amplification on the antitumor effect, selectively oncolytic agents, i.e., conditionally replicating adenoviruses, have been constructed. Infection of tumor cells results in replication, oncolysis and subsequent release of the virus progeny. Normal tissue is spared due to lack of replication. This review focuses on the various modifications tha...
Advances in adenoviral vectors for cancer gene therapy
Expert Opinion on Therapeutic Patents, 1997
Delineation of the molecular basis of cancer affords the possibility of specific intervention at the molecular level for therapeutic purposes. To this end, viral and non-viral vectors have been designed for delivery and expression of genes into target malignant and non-malignant cells. Gene transfer by available vectors, applied in both the ex vivo and in vivo contexts, has resulted frequently in the desired cellular phenotypical changes. In this regard, recombinant adenoviruses have been particularly efficient for in vivo gene transfer. Importantly, numerous human clinical protocols using adenoviruses have rapidly entered into Phase I clinical trials. However, major vector-related problems remain to be solved before the transfer of therapeutic genes by adenoviruses can become an effective and common place strategy for cancer treatment. An overriding obstacle is the basic ability to deliver therapeutic genes quantitatively, and specifically, into tumour cells. In addition, transgene expression in transduced target cells has not been prolonged enough for certain applications. The short-term expression is due both to the adenoviral non-integrative life cycle and to potent inflammatory and immunological responses against the vector and transgene. Here we review a number of diverse advances in the design of adenoviral vectors for overcoming these obstacles. As vector technology fulfils these requirements for obtaining the 'targetable-injectable' vector, it is anticipated that promising results already observed in preclinical studies will translate quickly into the clinic.
Gene therapy for cancer (present status)
Neoplasma
The present status of cancer gene therapy is reviewed here in short Two of the main gene therapy strategies for the treatment of cancer are discussed. The first main strategy is direct gene therapy which involves insertion of a functioning tumor suppressor gene or suppression of expression of a known oncogene. The second main strategy is indirect gene therapy which involves the insertion of a gene that modifies the cell to be more immunogenic for the host. The main clinical gene therapy trials are reviewed in their present state, including the replacement of defective tumor suppressor genes, the inser tion of suicide or sensitivity genes, the insertion of prodrug-activating genes, and the use of virally directed enzyme prodrug therapies. Other topics discussed are the protection of stem cells from toxic effects of chemotherapy and new directions for gene therapy of neoplastic disease.
Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy
Cancers, 2021
Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a ...