RNA Viruses as Tools in Gene Therapy and Vaccine Development

Abstract

RNA viruses have been subjected to substantial engineering efforts to support gene therapy applications and vaccine development. Typically, retroviruses, lentiviruses, alphaviruses, flaviviruses rhabdoviruses, measles viruses, Newcastle disease viruses, and picornaviruses have been employed as expression vectors for treatment of various diseases including different types of cancers, hemophilia, and infectious diseases. Moreover, vaccination with viral vectors has evaluated immunogenicity against infectious agents and protection against challenges with pathogenic organisms. Several preclinical studies in animal models have confirmed both immune responses and protection against lethal challenges. Similarly, administration of RNA viral vectors in animals implanted with tumor xenografts resulted in tumor regression and prolonged survival, and in some cases complete tumor clearance. Based on preclinical results, clinical trials have been conducted to establish the safety of RNA virus delivery. Moreover, stem cell-based lentiviral therapy provided life-long production of factor VIII potentially generating a cure for hemophilia A. Several clinical trials on cancer patients have generated anti-tumor activity, prolonged survival, and even progression-free survival.

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

“…Commonly used approaches include the direct substitution of structural genes with heterologous expression or placing the nonstructural genes downstream of the RNA sub-genomic promoter [117]. However, alphaviruses induce severe cytopathogenic effects, which restrict their application in gene therapy, although different strategies can be employed to surmount this challenge [118]. Some of these strategies include engineering of mutant vectors with mitigated cytotoxicity and temperature-inducibility, and self-inactivating vectors with point mutations in the nsP2 gene (especially at position 726, 259 and 650) [119].…”

Coronavirus Pandemic—Therapy and Vaccines

“…Viral vectors have been frequently used as delivery vehicles for immunization against infectious agents such as pathogenic viruses [159]. In many cases, strong humoral and cellular immune responses have been observed as well as protection against challenges with lethal doses of pathogenic viruses.…”

“…Finally, self-replicating RNA viruses have proven to be efficient as vaccine vectors due to the highly efficient replication of their ssRNA genome of positive polarity directly in the cytoplasm [159]. As vectors have been engineered allowing immunization of plasmid DNA replicons, naked RNA replicons or replication-deficient particles, the application range is wide.…”

Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy

“…Many other attempts to create safe and efficient viral vectors have been made. Alphaviruses, flaviviruses, picornaviruses, rhabdoviruses, and paramyxoviruses are among the viruses that have been tried as delivery vehicles in viral-based gene therapy [158]. However, these approaches have not yet been applied to RA therapy, and most of them do not appear as the best choice in the case of RA.…”