.:Research
Viral Vectors for Gene Therapy
Viral Vectors for Gene Therapy
?Sections:
Adenovirus Gene Therapy Vectors
The basic concept of gene therapy is simple: introduce into target cells a piece of genetic material that will result in either a cure for the disease or a slow-down in the progression of the disease. To achieve this goal, gene therapy requires technologies capable of gene transfer into a wide variety of cells, tissues, and organs. One of the biggest stumbling blocks to successful widespread application of such genetic treatments is the development of safe and effective vectors with which to ferry genetic material into a cell. The basic concept of viral vectors is to harness the innate ability of viruses to deliver genetic material into the infected cell. In general, the major preoccupation of viruses is to replicate and produce copious amounts of progeny. Most viruses gain little by killing the host, but unfortunately many viral infections lead to deleterious effects on the host, accompanied by destruction of infected cells. Damaging effects can be caused by induction of genes whose products are hazardous to the host or by acquiring host genomic material that can lead to pathogenesis. The basic principle of turning these pathogens into delivery systems relies on the ability to separate the components needed for replication from those capable of causing disease.
Turning viruses into vectors
The first step of viral vector design is to identify the viral sequences required for replication, assembly of viral particles, packaging of the viral genome, and delivery of the transgene into the target cells. Next, dispensable genes are deleted from the viral genome to reduce replication and pathogenicity, as well as expression of immunogenic viral antigens. The gene of interest together with transcriptional regulatory elements (referred to as the transgene) are inserted into the vector construct, and recombinant virus is generated by supplying the missing gene products required for replication and virion production. The more genes that are removed from the virus, the more replication defective the vector will be and the less chance of recombination to generate the infectious parental virus.
The nature of the virus biology will usually determine the means of production. For example retroviruses are produced in packaging cell lines and vector particles accumulate in the culture medium. In contrast adenovirus and AAV vectors are generally produced from transfections and cells must be lysed to liberate the viral particles.
Viral Vectors based upon many different viral systems, including retroviruses, lentiviruses, adenoviruses and adeno-associated viruses, currently offer the best choice for efficient gene delivery. Their performance and pathogenicity has been evaluated in animal models, and encouraging results form the basis for clinical trials to treat genetic disorders and acquired diseases. Despite some initial success in these trials, vector development remains a seminal concern for improved gene therapy technologies. Our lab believes that gaining an understanding of the basic biology of gene therapy viruses and their interactions with the host cell is critcial to the successful and rational design of novel gene therapy vectors.
