Table 1.

Immune responses in AAV gene therapy and possible strategies to modulate these responses

Immune responses	Mechanism	Strategy	Clinical status
Innate immunity	Evading TLR activation and DNA sensing	CpG depletion, CpG free ITRs	Preclinical
		TLR9-inhibitory DNA sequences	Preclinical
		Hydroxychloroquine	Preclinical
		DNA and RNA modification to ameliorate dsRNA and dsDNA	Preclinical
	Evading complement system	APL-9	Clinical trial
		Eculizumab	Clinical trial
	Reducing transgene expression in APCs	Proteasome inhibitor	Preclinical
		miRNA	Preclinical
Humoral immunity	Evading NAb formation	Excluding patients with pre-existing NAbs	Clinical trial
		Immunosuppressive drugs	Clinical trial
		ImmTOR	Clinical trial
		Antibody degrading enzymes	Preclinical
		Plasmapheresis	Clinical trial
		Saline flushing with or without balloon catheter	Preclinical
		Altering the route of administration	Clinical trial
	AAV-based strategies	Empty capsids	Preclinical
		Capsid engineering and modification	Preclinical
		Switching capsid variant	Preclinical
Cell-mediated immune responses	Systemic immune suppression	Immunosuppressive drugs	Clinical trial
	Reducing capsid presentation	Mutation of surface tyrosine	Preclinical
		Reducing therapeutic dose	Clinical trial
		Removing empty capsid	Preclinical
	Treg-based strategy	Tregitope	Preclinical
		ImmTOR	Clinical trial
		AAV-specific CAR Treg	Preclinical
Transgene immune responses	Systemic immune suppression	Immunosuppressive drugs	Clinical trial
	Tissue targeting	Tissue specific promoters	Preclinical
	Treg-based strategies	Polyclonal Tregs	Preclinical
		Transgene-specific CAR Treg	Preclinical
		Transgene-specific TRuC Treg	Preclinical
		BAR Treg	Preclinical
	Evading antibody-producing cells	BAR T cell	Preclinical

AAV adeno-associated virus, APCs antigen-presenting cells, BAR B-cell antibody receptor, CAR chimeric antigen receptor, ds double-stranded, ITRs inverted terminal repeats, miRNA microRNA, NAbs neutralizing antibodies, TLR toll-like receptor, Treg regulatory T cells