Table 3.

Preclinical studies of AAV-mediated gene therapy of brain diseases

Animal	Delivery	Targeted sites	Serotype	Transgene	Dosage (vg)	Ref
Parkinson’s disease
Rat	DI	Striatum	AAV2	AADC	2.5×1010	[25]
Rat	DI	Striatum	AAV2	AADC	4×1010	[164]
NHP	DI	Striatum	AAV2	AADC	3.6×1011	[165]
Rat	DI	STN	AAV2	GAD	1.0×108	[166]
NHP	DI	STN	AAV2	GAD	0.6–1.2×1010	[167]
Mouse	DI	Striatum	AAV9	miniSINEUP-GDNF	7.0×109	[168]
Rat	DI	Striatum	AAV5, AAV6	GDNF	3.0×108	[169]
Rat	DI	Striatum	AAV2	CDNF/GDNF	4.0×107, 2.0×108, 1.0×109	[170]
NHP	DI	Striatum	AAV2	GDNF	9.9×1011	[171]
NHP	DI	SN Striatum	AAV2	GDNF	5.5×1010, 5.5×1011	[172]
NHP	DI	Striatum	AAV2	NTN	3.0×1011	[173]
NHP	DI	Striatum	AAV2	NTN	1.7×1011	[174]
Mouse	DI	SN	AAV9	GBA1	2.0×1010	[175]
NHP	DI	SN	AAV9	GBA1	5.0×1010	[175]
Mouse	FUS-BBBO	HP/SN/OB/DMN	AAV9	shRNA	3.75×1011	[146]
Mouse	FUS-BBBO	STN Striatum	AAV1	GDNF	1.2×1011	[176]
Alzheimer’s disease
Mouse	DI	HP	AAV2/1	IL-10	3.0×109	[177]
Mouse	DI	HP	AAV2/1	IL-4	2.0×09	[178]
Mouse	DI	HP	AAV2/1	7ND	2.0×109	[179]
Mouse	ICV	Ventricle	AAV4	APOE2	1.0×1010	[180]
NHP	DI ICV ICM	HP Ventricle CM	AAVrh.10	APOE2	DI: 5.0×1012 ICV: 5.0×1013 ICM: 5.0×1013	[50]
Mouse	DI	HP	AAV8	IGF1/IGF2	NA	[181]
Mouse	IV	Left Heart Ventricle	AAV9	NEP	0.5–15×1011	[182]
Mouse	ICV	Ventricle	AAV1	Anti-Aβ scFvs	2.0×1010	[183]
Mouse	IN	NA	AAV2	CBD3	5.0×1011	[111]
Huntington’s disease
Rat	DI	Striatum	AAV2	GDNF	4.5 ×109	[184]
Rat	DI	Striatum	AAV2	BDNF and GDNF	1.4×1010	[185]
Mouse	DI	Striatum	AAV2/5	NeuroD1 or Dlx2	6.9 ×1010	[186]
Rat	DI	Striatum	AAV1/2	BDNF	2×109	[187]
Minipig	DI	Putamen thalamus	AAV5	miHTT	1–3×1013	[188]
Mouse	IV	NA	AAV-AS AAV9	miRHtt	5.0×1011	[73]
Mouse	DI	Striatum	AAV5 AAVrh10	CYP46A1	3×109	[189]
Canavan disease
Mouse	DI	Striatum thalamus	AAV2	ASPA	1.68×109	[190]
Rat	DI	Caudate thalamus	AAV2	ASPA	3.2×1010	[191]
Mouse	IV	NA	AAV9, rh.8, rh.10	ASPA	4.0×1011, 8.0×1011, 1.2×1012, 4.0×1012	[192]
Mouse	IV ICV	NA	AAV9, rh.8, rh.10	ASPA	IV:4.0×1011 ICV:2.0×1010	[193]
Mouse	IV	NA	AAV9	ASPA	4.0×1010, 1.33×1011, 4.0×1011	[194]
Lysosomal storage disease
Rat NHP	DI	Rat: Striatum NHP: Striatum	AAVrh.10	hCLN2	Rat：1.0×1011 NHP:1.8×1012	[195]
Mouse	DI	Multiple sites	AAV1	hCLN2	6.0×1010	[196]
Rat	DI	Striatum	AAV2, 5, 8, rh.10	hCLN2	2.5×109	[197]
Mouse	DI	Multiple sites	AAV2, AAV5	hCLN2	3.6×109	[198]
Mouse	DI	Striatum	AAV5	TPP-I	5.0×109	[199]
Mouse	ICV	Ventricle	AAV8	IDUA	2.0×1010	[200]
Mouse	IT or IV	NA	AAV2	IDUA	4.0×109 to 4.0×1010	[201]
Cat	ICM	Cisterna magna	AAV9	IDUA	1.0×1012/kg	[202]
Mouse	IN	NA	AAV9	IDUA	2.0×1011	[103]
Mouse	IN	NA	AAV8	IDUA	9.3×1010	[109]
Mouse	ICV	Ventricle	AAV9	IDS	3×108, 3×09, 3×1010	[203]
Mouse	DI	Striatum	NA	βgluc	1.0×107	[204]
Mouse	ICV	Ventricle	AAV5	Adbgluc/Adbgal	2.0×107	[54]
Dog	IT IV	NA	AAV9 AAVrh.10	GUSB	IV: 2.0×1013/kg IT: 5.0 or 2.8×1012/kg	[205]
Mouse	IV	NA	AAV9 AAVPFG	βgluc	1.0×1012	[206]
Dog	ICM	CM	AAV9	rβGpA	2.0 × 1013	[207]
Mouse Dog	ICV ICM	Ventricle CM	AAV9	Sgsh	Mouse: 5.0×109 or 5.0×1010 dog: 2.0×1013	[208]
Mouse	ICM IV	CM	AAV2	hNaGlu	IV:4.0×1011 ICM:5.0×1010	[53]
Mouse	ICM	CM	AAV9	Gns	5.0×1010	[209]
Mouse	DI	Thalamus or Thalamus & DCN	AAV2/1	GLB1	4.8×1010, 7.2×1010	[210]
Mouse	IV	NA	AAV9	GLB1	1.0×1011, 3.0×1011	[211]
Mouse	DI ICV	DI: Thalamus ICV: Ventricle	AAVrh.8	cmHexa cmHexb	1.1×1011, 3.2×1011, 3.2×1012	[212]
Mouse	DI	DCN	AAV1, 2, 5, 7, 8	ASM	1.86×1010	[213]
Mouse	IV	NA	AAV9	NPC1	1.2–1.3×1012	[214]
Sheep	ICM	CM	AAVrh.8	HEXA HEXB	1×1014, 5×1013	[48]
Rett syndrome
Mouse	IV	NA	AAV9	MECP2	1×1012	[215]
Mouse	P0–3: DI 4–5 wks.: IV	NA	AAV9	MECP2	DI: 4.8 × 1010 IV: 1.0 × 1011 ,5.0 × 1011	[216]
Mouse	P0–3: DI 4–5 wks.: IV	NA	AAV9	MECP2	DI: 4.8 × 1010 IV: 1.0 × 1011 ,5.0 × 1011	[217]
Mouse	ICM	CM	AAV9	MECP2	1.0×1012	[218]
Mouse	IV	NA	AAV9	MCO	2.0 × 1011	[219]
Mouse	IV	NA	AAV-PHP.eB	iMECP2	1.0×109–1.0×1012	[220]
Mouse	IT and ICM	CM	AAV9 PHP.B	miniMECP2	1×1012	[221]
Mouse	IV	NA	AAV9	MCO	1× 1011 ,5 × 1011,1 × 1012	[222]
Fragile X syndrome
Mouse	DI	HP	AAV5	FMR1	1×109	[223]
Mouse	ICV	Ventricle	AAV9	FMR1	1×109	[224]
Mouse	ICV	Ventricle	AAV9	FMR1	0.375–1×109	[225]
Mouse	ICV	Ventricle	AAV2/9	FMR1	1×109	[226]
Mouse/Rat	ICV, ICM	ICV: Ventricle	AAV9	FMR1	NA	[227]
Mouse	DI, IV	DI: Striatum, HP IV: Retro-bulbar space	DI: AAVrh.10 IV:AAV-PHP.eB	DGKk	DI: 2.5×109 ,IV: 8×108	[228]
Mouse	IV	NA	AAV-PHP.eB	FMR1	5×1013	[229]
Mouse	IT	NA	NA	FMR1	1.3×1011 ,2.3×1011, 5.0×1011	[230]
Dravet Syndrome
Mouse	ICV, ICM	Ventricle, CM	AAV9	NaVβ1	8.0×1010	[231]
Mouse	ICV	Ventricle	AAV9	REGABA-eTFSCN1A	1.7×1010–5.1×1010	[232]
NHP	ICV	Ventricle	AAV9	REGABA-eTFSCN1A	4.8×1013–8×1013	[232]
Mouse	ICV	Ventricle	AAV9	SCN1A-dCas9A	5.0×1013	[233]
Mouse	IV	NA	AAV-PHP.eB	SCN1A-dCas9A	1.8×1011	[234]
Angelman syndrome
Mouse	DI	HP	AAV9	UBE3A	1.5×109	[235]
Mouse	ICV	Ventricle	PHP.B	UBE3A	1.6×1011	[236]
Mouse	DI	DI: HP ICV: Ventricle	AAV9	STUB	2.0×1011	[237]
Rat	DI, ICV	DI: HP ICV: Ventricle	AAV9	UBE3A/STUB	UBE3A DI: 4.0×1010 UBE3A ICV: 2.0×1011 STUB DI: 6.8×1010 STUB ICV: 3.0×1011	[237]
Mouse	ICV	Ventricle	AAV9	UBE3A-ATS SpCas9	1.5×1010	[238]
Mouse	ICV,IV	ICV:Ventricle	ICV:hu68 IV: PHP.B	UBE3A-ATS-dCas9	ICV: 1.0×1011 IV: 1.0×1012	[239]
Mouse	IV	NA	PHP.eB	ATF-S1K	1.0×1012	[240]

DI: Direct intraparenchyma injection; IN: Intranasal delivery; ICV: Intracerebroventricular injection; IT: Intrathecal injection; ICM: Intra-cisterna magna injection; IV: Intravenous injection; FUS-BBBO: Focused ultrasound with microbubble-induced BBB opening; STN: Subthalamic nucleus; SN: Substantia nigra; HP: Hippocampus; OB: Olfactory bulb; DMN: Dorsal motor nucleus of the vagus; CM: Cisterna magna; DCN: Deep cerebellar nuclei.