Immunogenicity and toxicity of AAV gene therapy

Abstract

Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.

Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

“…The advantages of this higher targeting specificity are two-fold. First, high AAV concentrations are associated with toxicity due to AAVinduced adaptive immune response 40 . Second, AAV production is a time-consuming and costly (which was not certified by peer review) is the author/funder.…”

“…To remove cell debris, the samples were centrifuged at 4000 g and the supernatant was collected. The supernatant was loaded over 4 layers of iodixanol gradient solution (15,25,40 and 60%), followed by a centrifugation for 2.5 h at 50000 rpm in a 70Ti rotor. Fractions were collected and those corresponding to the interface of 40 and 60% were pooled, buffer exchanged and concentrated.…”

Adding recombinant AAVs to the cancer therapeutics mix

“… 5 , 8 , 9 , 101 , 102 , 103 Even in reports of hemophilia A where a high dose of an rAAV driving expression of factor VIII is inducing immune responses, such as neutralizing antibodies toward the AAV capsid, strategies to dampen the immune response to the virus or enhance the efficacy of the rAAV are showing promise and could be broadly applicable. 97 , 104 , 105 , 106 Other types of viral vectors and nucleic acid-based methods of gene therapy being explored do not consistently exhibit these characteristics of low immunogenicity or no links to human pathology, making AAVs an attractive vehicle for gene therapy. Moreover, rAAVs convey long-term expression of the transgene and are versatile as their genomes are easily manipulated and altered to meet the needs of specific studies and pathologies.…”

Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

“…Thus, reducing the vector dose is one important aspect of ensuring the safety of AAV-based gene therapy. [11][12][13] Another problem with AAV vectors is the patient's immune status against AAV. Like the naturally occurring anti-AAV-neutralizing antibodies (NAbs) attenuates AAV-mediated gene therapy, 14,15 induction of NAbs after an AAV vector administration deprives a chance to re-administrate the same serotype of the AAV vector.…”