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. 2021 Oct 29;12:753467. doi: 10.3389/fimmu.2021.753467

Table 1.

Summary of immune responses to AAV gene therapy and evasion/prevention strategies.

Response Strategy to evade them
Pre-existing nAbs against the capsid (35, 71, 72)

  • previous exposure to wtAAVs

 Host

  • exclusion from clinical trials (71)

  • route of administration (73), saline flushing (74)

  • immune-privileged organ (75, 76)

  • nAb depletion [plasmapheresis (77), immunoadsorption (78), (IgG)-degrading enzymes (79)]
Vector

  • novel serotype selection (80)

  • AAV capsid engineering (81, 82)

  • chemical modification of the capsid (83)

Pre-existing nAbs against the transgene

  • previous exposure to recombinant or truncated protein (84)

 Host

  • targeting of tolerogenic organs (85)
Activation of the innate system

  • vector capsid (55)/genome (51, 58)/dsRNA (64) sensing

  • CpG containing vector genome (57, 59, 63)

 Vector

  • CpG depletion (67)

  • TLR9-inhibitory sequences addition (86)

  • suppression of ITR promoter activity (70)
nAbs against the capsid after gene therapy (79, 87) Host

  • targeting of tolerogenic organs (88)

  • induction of tolerance (89)

  • B-cell depletion (90)
Vector

  • vector engineering to avoid antigen presentation (91)

nAbs against the transgene after gene therapy (59, 62, 87)

  • null or missense mutations (92–94)

  • route of administration (92)

 Host

  • targeting of tolerogenic organs (37, 95–97)

  • immune suppression (98)

  • B-cell depletion (90)
Vector

  • tissue-specific expression (promoter, miRs) (99, 100)

Cellular immune responses against the capsid (39, 101)

  • route of administration (102, 103)

  • vector dose (101)

 Host

  • immune suppression (27, 98, 101)

  • targeting of immune-privileged organs (102, 103)

  • targeting of tolerogenic organs (104), induction of tolerance (89, 105)

  • cell-type specific expression (promoter, miRs)
Vector

  • vector selection/engineering to avoid antigen presentation (106–108)

Cellular immune responses against the transgene

  • route of administration (92, 109)

  • vector dose (110)

 Host

  • immune suppression (98, 111)

  • targeting of immune-privileged organs (37)

  • targeting of tolerogenic organs (104), induction of tolerance (97)

  • restriction of transgene expression (promoter, miRs) (100)
Vector

  • vector engineering to avoid antigen presentation (112)

Vector dose (toxicity) Host

  • lower vector dose

  • capsid/transgene optimization for increased expression