The VRX496 Phase I trial involves the use of a HIV-based lentiviral vector where a muted or "gutted" form of the virus is genetically engineered to inhibit HIV replication and spread. T-cells from HIV-infected patients are removed and treated with the HIV lentiviral vector and then are reintroduced into the patient. The goal for this new potential therapy for HIV/AIDS is to place the disease into permanent remission by creating an army of VRX496-containing CD4 T-cells in the patient's body that permanently suppresses HIV infection. The market for gene therapy approaches is expected to be $60 billion in 2005. Gene therapy involves the insertion of a functional gene or another molecule that contains an information sequence into a cell to achieve a therapeutic effect. Somatic cell gene therapy is intended to eliminate the clinical consequences of a disease, and the inserted gene is not passed on to the patient's offspring. Before 1996 scientists relied mainly on modified retroviruses such as Moloney murine leukemia virus when gene transfer into the chromosomes of target cells was needed, and adenovirus vectors when such integration was not needed. However, there has been limited success in gene transfer with such virus vectors because even though the vectors can enter into their target cells, the cells need to be dividing, so that the nuclear membrane is broken down and the gene can enter and integrate into the chromosome. However, scientists soon realized that members of the subfamily lentivirus, such as the retrovirus HIV, would have the same ability to transfer genetic material into the genomes of cells but could do this with non-dividing, dormant cells in vivo and growth-arrested cells in vitro. Exploring this new method of gene therapy has been the work of many labs in the past few years.

Lentiviral vectors are able to infect both dividing and non-dividing cells because their pre-integration complex (virus "shell") can get through the intact membrane of the nucleus of the target cell. Lentiviruses can be used to provide highly effective gene therapy as lentiviruses can change the expression of their target cell's gene for up to six months. They can be used for non-dividing or terminally differentiated cells such as neurons, macrophages, hematopoietic stem cells, retinal photoreceptors, and muscle and liver cells, cell types for which previous gene therapy methods could not be used. HIV is a very effective lentiviral vector because it has evolved to infect and express its genes in human helper T-cells and other macrophages. The only cells lentiviruses cannot gain access to are quiescent cells because this blocks the reverse transcription step.

Another company working on lentiviral vectors is Oxford BioMedica which holds key patents for lentiviral gene therapy techniques. Its proprietary LentiVector® technology patent is primarily targeted at neurological disorders such as Parkinson's disease which has a market value of $1.8 million. The BioMedica team was the first to construct lentiviral vectors that contain no viral genes at all and which comprise the minimum number of viral components in the viral particles. They have used vectors based on HIV and Equine Infectious Anemia Virus (EIAV), a horse virus that is not linked to any disease in humans. The EIAV system is BioMedica's system of choice because of its superior safety profile. Oxford BioMedica is currently utilizing the EIAV-based vector system in target validation and gene discovery and in preclinical studies in therapies for prostate cancer and Parkinson's disease. In particular, BioMedica has shown that LentiVector has a unique capability for the delivery of genes at high efficiency to cells of the nervous system. This capability underlies BioMedica's candidate Parkinson's disease product ProSavin® and will be one of the main areas of focus for BioMedica Inc., Oxford BioMedica's new U.S. operation.

At the end of March 2004, Oxford BioMedica was awarded #0.5 million from the U.K. Department of Health Gene Therapy Research Programme. The award is to encourage development of the proprietary LentiVector technology for use in the treatment of single gene inherited disorders. The focus of the work is to be hemophilia A, a condition caused by a defective gene for Factor VIII, a key component of the mechanism for forming blood clots. Three years ago the Company initiated a program to develop a product known as Requinate(TM). Requinate comprises a LentiVector gene delivery system carrying a modified version of the human Factor VIII gene. During this exploratory program, the Company solved several problems that had been encountered by others attempting gene therapy for hemophilia. However, since hemophilia falls outside of the Company's therapeutic focus of cancer and neurotherapy, the program has received minimal internal resources. The new money from the Department of Health will enable the Company to progress the Requinate hemophilia program without compromising progress of its cancer and neurotherapy products. The current market for Factor VIII treatment is in excess of $1.0 billion.

The versatility of lentiviral vectors makes them a useful tool in a number of applications such as gene therapy, transgenesis, stem cell manipulation, somatic disease models, target validation, and gene discovery. There are still safety concerns when using lentiviral vectors. One concern involves the possibility that the virus could self-replicate and could be produced during manufacture of the vector in the packaging cell line or in the target cells by a process of recombination. Thus, the person undergoing gene therapy would also be infected with the virus in addition to the new therapeutic gene. A self-replicating infectious vector could cause cancer by inserting itself into the host genome and activating a neighboring proto-oncogene, thus causing mutagenesis. However, the modern approaches demonstrated by VIRxSYS and Oxford BioMedica as well as early results from clinical trials suggest that the future for lentiviral vectors is likely to be positive.