Immune Responses to Viral Gene Therapy Vectors

Abstract

Several viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, with many more in pre-clinical testing. Efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive. In fact, viral vector gene therapy has been able to treat or even cure diseases for which there had been no or only suboptimal treatments. However, innate and adaptive immune responses to these vectors and their transgene products constitute substantial hurdles to clinical development and wider use in patients. This review provides an overview of the type of immune responses that have been documented in animal models and in humans who received gene transfer with one of three widely tested vector systems, namely adenoviral, lentiviral, or adeno-associated viral vectors. Particular emphasis is given to mechanisms leading to immune responses, efforts to reduce vector immunogenicity, and potential solutions to the problems. At the same time, we point out gaps in our knowledge that should to be filled and problems that need to be addressed going forward.

Therapeutic Effects of Genetically Modified Wharton’s Jelly Mesenchymal Stem Cells Expressing Erythropoietin on Cancer-related Anemia in Mice Model

“…The erythropoiesis response to therapy was proportional to the dose of plasmid DNA or viral vectors delivered. Moreover, host immune responses to these vectors and their transgene products are associated to potential health risks limiting their entry into the clinical phase (13,42).…”

“…Gene therapy via designing the plasmid DNA and viral vectors encoding the EPO gene introduced an attractive research area for treating anemia. In preclinical studies, gene therapy for direct delivery of EPO gene into animal models' skeletal muscle has shown a signi cant increase in EPO and erythropoiesis; however, life-threatening polycythemia and host immune responses to viral vectors limit its utilization in the clinic (13,14). Cell-based therapies were studied as a treatment option in animal and clinical phases since 1990, which showed the satisfactory safety and e cacy pro les (15)(16)(17).…”

Adenoviral Vectors Meet Gene Editing: A Rising Partnership for the Genomic Engineering of Human Stem Cells and Their Progeny

“…As it came to be known, the E1 deletion does not fully prevent residual expression from some of the transcriptional units that remain in vector genomes [71]. The resulting leaky synthesis of viral gene products leads to vector dose-dependent cytotoxicity in vitro and short-lived transgene expression in vivo (2-3 weeks) due to the clearance of transduced cells by the immune system [90]. For this reason, E1-deleted AdVs, in particular those based on serotypes with low seroprevalence in the human population, are being applied in clinical trials not for gene therapies requiring prolonged transgene expression but as vaccination agents instead, e.g., against hemorrhagic fever and AIDS caused by Ebola and HIV-1 infections, respectively [91,92].…”

Host immune responses after suprachoroidal delivery of AAV8 in nonhuman primate eyes

“…[10][11][12][13] Also, cell-mediated immune responses from cytokinesecreting T-cells can directly destroy transduced cells. 14 Together, host humoral and cellular immune responses contribute to eliminating vectors and transduced cells, thus limiting the therapeutic effect.…”