Adenovirus-Mediated Gene Transfer to Treat Neurologic Disease

Abstract

ithin the last 10 years the development of tools used to manipulate DNA have shown promise in the generation of a new form of therapeutic intervention known as gene therapy. Gene therapy involves the introduction of genetic material into cells to replace or supplement defective genes or to induce the expression of a novel gene to help alleviate a disease. These manipulations can be done in cells either outside the body and transplanted back in (ex vivo gene therapy) or directly within a specific target organ (in vivo gene therapy). To target and transfer DNA or RNA to cells a variety of techniques have been developed, including the use of replication-defective viruses, lipid bilayers that encapsulate DNA (liposomes), and DNA-coated gold particles that are ballistically shot into cells (gene gun). Most of these topics will be discussed in articles to follow in this series. Call for Papers Call for Papers Neuro-Oncology The ARCHIVES is planning a theme approach to neuro-oncology for the April 1999 issue. Papers are requested for consideration that represent new and important information related to brain tumors. Both clinical and basic science subjects are requested. Manuscripts must be received prior to November 1 to allow for appropriate consideration.

New Treatment Strategies for Malignant Gliomas

“…Adenoviruses are highly stable, nonenveloped, double-stranded DNA-containing viruses with a low rate of genomic instability and, therefore, low risk of insertional mutagenesis. Adenoviruses transfer their DNA by binding to a specific cell surface receptor, entering the cytoplasm by endocytosis, and then forming a pore in the endosome to translocate genetic material to the nucleus [86].…”

“…Although the transduction process alone is not cytotoxic, cellular production of thymidine kinase confers susceptibility to those cells subsequently exposed to ganciclovir. The so-called "bystander effect" is the result of diffusion of phosphorylated nucleosides away from dying cells to adjacent nontransduced tumor cells resulting in their death [86].…”

“…D) After dialysis, replication-defective adenovirus can be used for in vivo transfections. Used with permission from [86].…”

Adenoviral Vector-Mediated Gene Transfer for Human Gene Therapy

“…Recently, the efficacy of adenoviral vectors has been demonstrated in several models of neurodegenerative diseases including Parkinson's disease (PD) and motor neuron diseases (Barkats et al, 1998;Smith, 1998). In rat PD models, adenoviral vectors expressing either tyrosine hydroxylase, superoxide dismutase or glial-derived neurotrophic factor improved the survival and functional efficacy of dopaminergic cells .…”

New Molecular Strategies to Cure Brain Tumors

“…The current status and limitations and the future directions of adenoviral-and retroviral-mediated gene transfer have recently been discussed in the "Basic Science Seminars in Neurology" section of the ARCHIVES. 1,2 Suicide gene therapy for malignant brain tumors has been tested in humans. An example is the transfer into malignant cells of the herpes simplex thymidine kinase (HSV-tk) gene, which converts the nontoxic nucleotide analog ganciclovir into phosphorylated compounds that halt transcription of DNA in dividing cells.…”