Immune responses to AAV vectors: overcoming barriers to successful gene therapy

Abstract

Gene therapy products for the treatment of genetic diseases are currently in clinical trials, and one of these, an adeno-associated viral (AAV) product, has recently been licensed. AAV vectors have achieved positive results in a number of clinical and preclinical settings, including hematologic disorders such as the hemophilias, Gaucher disease, hemochromatosis, and the porphyrias. Because AAV vectors are administered directly to the patient, the likelihood of a host immune response is high, as shown by human studies. Preexisting and/or recall responses to the wild-type virus from which the vector is engineered, or to the transgene product itself, can interfere with therapeutic efficacy if not identified and managed optimally. Small-scale clinical studies have enabled investigators to dissect the immune responses to the AAV vector capsid and to the transgene product, and to develop strategies to manage these responses to achieve long-term expression of the therapeutic gene. However, a comprehensive understanding of the determinants of immunogenicity of AAV vectors, and of potential associated toxicities, is still lacking. Careful immunosurveillance conducted as part of ongoing clinical studies will provide the basis for understanding the intricacies of the immune response in AAV-mediated gene transfer, facilitating safe and effective therapies for genetic diseases.

Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

“…1,2,10,12 Despite the excellent safety and efficacy profile, however, some important limitations of the technology remain, mainly associated with the need for more efficient vectors that can escape, to some extent, recognition by the host immune system. 3 Here, we demonstrated that exosome-enveloped AAV vectors offer a feasible, relatively simple strategy to achieve superior correction of hemophilia via enhanced targeting of hepatocytes, at the same time providing protection from preexisting NAbs. Although the mechanism of enhancement of transduction is not completely understood, based on our in vitro results, exo-AAV vectors seem to present a faster nuclear translocation rate, which may be the result of more efficient and autophagy-independent 22 intracellular trafficking.…”

“…3 Recombinant AAV vectors are derived from their wildtype counterpart, 4 which naturally infects humans. Because AAV infection in nature occurs in the context of a helper virus, humans develop both neutralizing antibodies (NAbs) 5,6 and memory T-cell reactivity 7,8 directed against the capsid.…”

2017 White Paper on Recent Issues in Bioanalysis: A Global Perspective on Immunogenicity Guidelines & Biomarker Assay Performance (Part 3 – Lba: Immunogenicity, Biomarkers and PK Assays)

“…One of the significant challenges related to development of the viral gene therapy modality is potential impact of pre-and post-administration immunogenicity. A suite of immunogenicity assays should be considered in support of a gene therapy product, including pre-and post-administration immune responses against viral capsid, transgene product and transfected cells (only if using allogeneic cells but not if autologous cells are used) [43][44][45].…”

Development of Optimized AAV Serotype Vectors for High-Efficiency Transduction at Further Reduced Doses

“…[1][2][3][4][5][6][7][8][9] However, in some cases, the use of large vector doses to achieve therapeutic benefits has also been shown to trigger the host immune response to the capsid proteins. 10 In the first clinical for the potential gene therapy of hemophilia B, AAV2 serotype vectors failed to express therapeutic levels of human factor IX (hF.IX) at a dose of 10 13 vg in a patient. When the dose was increased to 10 14 vg, AAV2 vectors did express the therapeutic level of hF.IX.…”

“…10 In the first clinical for the potential gene therapy of hemophilia B, AAV2 serotype vectors failed to express therapeutic levels of human factor IX (hF.IX) at a dose of 10 13 vg in a patient. When the dose was increased to 10 14 vg, AAV2 vectors did express the therapeutic level of hF.IX. However, such a high vector dose also induced a cytotoxic T-cell (CTL) response against the capsid proteins.…”