Viral Vectors in Gene Therapy: Special Emphasis on Alphaviruses

Viral Vectors in Gene Therapy: Special Emphasis on Alphaviruses

Speaker: Kenneth Lundstrom

Affiliation: PanTherapeutics, Lausanne, Switzerland

Host: Manuel T. Carrondo

Abstract:

Viral vectors have showed some promise in various areas of gene therapy. The cure of severe combined immune deficiency (SCID-X) patients with retrovirus vectors can be considered as a major breakthrough. Treatment of hemophilia, CNS-related diseases and especially cancer has been other common approaches. Particularly, adenovirus, adeno-associated virus (AAV) and lentivirus vectors have been frequently applied. However, less commonly used, alphavirus vectors provide interesting properties for gene therapy applications.

Alphaviruses are enveloped viruses with a single-stranded RNA genome. Semliki Forest virus (SFV), Sindbis virus (SIN) and Venezuelan Equine Encephalitis virus (VEE) have been developed as expression vectors. The following three types of expression systems have been engineered: 1. Replication-deficient vectors, which allows one round of infection followed by high expression levels of heterologous proteins due to deletions in the viral genome. 2. Replication-competent vectors, which provides production of progeny virus and thereby spread of full-genome infectious particles. 3. DNA-layered vectors, which provide transient delivery of the gene of interest in a plasmid vector carrying alphavirus replicase genes.    

Alphavirus vectors have been frequently used in recombinant gene expression and in neuroscience due to their broad range and high expression level. Moreover, alphaviruses have been subjected to vaccine generation against tumor and viral challenges. SFV vectors have also been used for gene therapy applications. For instance, intratumoral injection of replication deficient particles has demonstrated tumor regression in mouse models. Recently, oncolytic replication-proficient SFV vectors have been evaluated in nude mice models for lung cancer and osteosarcoma with some promising results. Sindbis virus has demonstrated a remarkable natural targeting to tumors in animal models, which has supported systemic delivery approaches. Another approach to allow systemic administration has been the eEncapsulation of SFV particles in liposomes, which results in passive targeting of tumors and allows repeated virus administration as the encapsulated particles are not recognized by the host immune system. Encapsulated SFV particles expressing interleukin-12 (IL-12) were subjected to a phase I clinical trial in melanoma and kidney carcinoma patients. The study suggested safe use of encapsulated SFV particles in humans.