Advantages of HSV Vectors

Although each viral gene transfer vector possesses distinct attributes, successful gene therapy will require construction of gene transfer vectors that are tailored to specific applications. The human herpes viruses represent promising candidate vectors for several types of gene therapy applications that include neuropathological disorders, cancer, pain control, autoimmune syndromes, and metabolic diseases.

Herpes viruses are large DNA viruses, with the potential to accommodate multiple transgene cassettes, that have evolved mechanisms that allow lifelong persistence in a nonintegrated latent state without causing disease in an immune-competent host. Among the herpes viruses, HSV-1 is an attractive vehicle for gene transfer to the nervous system because natural infection of humans results in a usually benign, lifelong persistence of viral genomes in neurons. This latent state is characterized by the absence of lytic viral protein expression, and the pres ence of these latent genomes does not alter nerve cell function or survival. The HSV-1 genome contains a unique, neuron-specific promoter complex that remains active during latency, the latency active promoter (LAP). This promoter can be adapted to express therapeutic proteins without compromising the latent state or stimulating immune rejection of transduced cells. The establishment of latency does not appear to require the expression of viral lytic functions. Essential genes required for expression of the viral lytic functions can therefore be deleted to create completely replication-defective vectors that nonetheless effectively establish a latent state, but cannot cause disease or reactivate from latency. Experimental HSV infection is not limited to neurons; the virus is capable of infecting most mammalian cell types, and does not require cell division for infection and gene expression. Accordingly, HSV may be generally useful for gene transfer to a variety of nonneuronal tissues, particularly where short-term transgene expression is required to achieve a therapeutic effect.

Considerable technical progress has been made in developing HSV-1 into a practical gene transfer vector, including the development of efficient methods for vector construction and high-titer vector production. The obstacles requiring satisfactory resolution in order to realize the full potential of these vectors include (1) the elimination of vector toxicity, (2) the design of promoter cassettes that provide for sufficient level and duration of transgene expression, and (3) targeting of transgene expression to specific cell populations through the use of tissue-specific promoters, or by altering the virus host range through modifying receptor utilization for attachment and entry. This chapter concentrates on the design, production, and utilization of replication-deficient genomic HSV vectors.

0 0

Post a comment