Table 2.

Adeno-associated viral vectors for brain-targeted gene delivery

Type	Gene	Disease/Mechanism	Transduced Cell Types	In Vitro Cell Source	In Vivo	Result	Reference
AAV1	Galactocerebrosidase (GALC)		Neurons, Astrocytes, Oligodendrocytes	Humans, mice	Twitcher (Twi) mice	Stable expression in vivo, improved myelination, symptom reduction, and increased life span	(Rafi et al., 2005)
AAV1 AAV2	Green fluorescent protein (GFP)	Neurodegenerative diseases and disorders (NDDs)	Neurons, Astrocytes, Oligodendrocytes, Microglia		C3H/HeJ mice	AAV1 transduced multiple cell types, higher efficiency and better distribution than AAV2	(Wang et al., 2003a)
AAV1 AAV2 AAV8	CNTF	Myelin disorders	Sensory neurons, Schwann cells		CD-1 mice	AAV8: preferential Schwann cells transduction, lower immunogenicity, increased myelin and neuronal proteins associated with axonal regeneration	(Homs et al., 2011)
AAV1 AAV5 AAV9 AAVrh10	GFP	SCI	Neurons, Astrocytes Oligodendrocytes		SD rats	AAVrh10: Neuronal transduction efficiency was similar to other vectors but also transduced other cell types	(Petrosyan et al., 2014)
AAV1 AAV8 AAV9	GFP		Neurons, Astrocytes, Purkinje Cells		B6 mice	AAV9 most effective and sustained global expression for 18 months	(Miyake et al., 2011)
AAV2	B-cell lymphoma 2-like 2 (a.k.a. Bcl-w)	Cerebral ischemia	Neurons, Astrocytes, Ependymal Cells		MCAO in SD rats	Global expression, infarct size reduction, improved neurological function	(Sun et al., 2003)
	GFP		Neurons, Microglia		SD rats	Neuronal expression 3 days post-infusion	(Bartlett et al., 1998)
	GFP		Neurons, Astrocytes	N/S	Wistar rats	Human synapsin promoter: neuronal expression in vitro, in vivo Cytomegalovirus promoter: glial expression in vitro, thalamic neurons in vivo	(Kügler et al., 2003)
	GFP		Neurons, Astrocytes		Cynomolgus monkeys	Neuronal expression and astrocyte activation	(An et al., 2016)
	GFP		Oligodendrocytes	Rats type N/S	B6 mice	Expression in white matter in vivo, oligodendrocytes in vitro due to inclusion of myelin basic protein promoter	(Chen et al., 1998)
AAV2 AAV5	GFP, Luc	NDDs	Neurons, Astrocytes		Kainate-treated SD rats	Kainate-induction reduced transduction efficiency; AAV5 better than AAV2; AAV5 glial transduction in seizured brains	(Weinberg et al., 2011)
	LacZ		Neurons, Astrocytes	Wistar rats	Gerbils	In vitro: AAV2 neuronal tropism, AAV5 astrocyte tropism; In vivo: higher AAV5-mediated hippocampal expression	(Nomoto et al., 2003)
	LacZ, Red fluorescent protein (RFP)	NDDs	Microglia	Wistar rats	SD rats	F4/80 promoter provided the best specificity compared to CD11b, CD68 promoters	(Cucchiarini et al., 2003)
AAV2, AAV6	GFP		Astrocytes, Muller cells	Humans, rats	Fischer 344 rats	Higher efficiency in vitro, astrocyte, muller glia transduction ability in vivo of AAV variants generated by loop replacement	(Koerber et al., 2009)
	GFP		Astrocytes		Human retinas, Crb1−/− mice	Astrocyte-expression with glial fibrillary acidic protein (GFAP) promoter	(Aartsen et al., 2010)
AAV2 AAV9	GFP, L-amino acid decarboxylase		Astrocytes		SD rats, Cynomolgus monkeys	AAV2, but not AAV9, mediated protein expression without immune response	(Ciesielska et al., 2013; Samaranch et al., 2014)
AAV4	GFP, LacZ		Astrocytes, Neuronal progenitor cells		C57/BL6 mice	Expression in ependymal cells, astrocytes of subventricular zone, rostral migratory stream	(Liu et al., 2005)
AAV5	GDNF	PD	Astrocytes		MPTP-induced B6 mice, 6-OHDA-treated Wistar rats	Expression specific to the injected hemisphere, no off-target effects; same efficacy as neuron-derived GDNF; increased DA synthesis, behavioral improvement	(Drinkut et al., 2012)
	VIVIT, a peptide that interferes with the calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway	Alzheimer’s disease (AD)	Astrocytes		Amyloid precursor protein/presenilin-1 mice	Reduced glial activation, amyloid levels, improved cognitive and synaptic function	(Furman et al., 2012)
AAV8 AAVcy5 AAVrh20 AAVrh39 AAVrh43	GFP		Neurons, Astrocytes, Oligodendrocytes		SD rats	Preferential astrocyte and oligodendrocyte transduction with AAV8 and AAVrh43 using cell-specific promoters	(Lawlor et al., 2009)
AAV8, AAV9	GFP, mCherry		Neurons, Astrocytes		B6 mice	AAV8 astrocyte tropism and AAV9 neuronal tropism; single complementary (sc) AAV better than single strand (ss) AAV	(Aschauer et al., 2013)
AAV9	Erythropoietin (EPO)	PD	Neurons, Astrocytes		6-OHDA treated SD rats	Prior intramuscular injection reduced intrastriatal transduction efficiency due to circulating antibodies to AAV and EPO	(Yang et al., 2013)
	GFP	Amyotrophic lateral sclerosis	Neurons, Astrocytes		B6 mice	Crosses blood-brain barrier, neonatal mice: neuronal tropism, adult mice: astrocyte tropism	(Foust et al., 2009)
	GFP	Spinal muscular atrophy (SMA)	Motor neurons, Astrocytes		Survival motor neurons Δ7 and B6 mice	Intramuscular injection transduced spinal cord motor neurons, astrocytes; increased median lifespan	(Benkhelifa-Ziyyat et al., 2013)
	GFP	SMA	Neurons, Astrocytes, Oligodendrocytes		Cynomolgus monkeys	Global CNS expression at different ages; selective CNS expression by cerebrospinal fluid delivery	(Bevan et al., 2011)
	GFP		Neurons, Astrocytes		BALB/C mice, Rhesus macaques	Higher neuronal expression in rodent, higher glial expression in NHPs, scAAV efficient than ssAAV	(Gray et al., 2011)
	GFP		Neurons, Astrocytes		MF1 mice	Neuronal tropism in fetal mice, astrocyte tropism in neonatal mice; ssAAV efficient than scAAV	(Rahim et al., 2011)
	GFP		Neurons, Astrocytes		B6 mice	Neonatal mice: astrocyte tropism; young mice: neuronal tropism	(Gholizadeh et al., 2013)
	GFP		Neurons, Astrocytes		B6 mice	Intrathecal delivery efficient than intravenous delivery	(Schuster et al., 2015)
	GFP		Neurons, Astrocytes		SD rats, farm mice	Dose-dependent increase in global transduction, no astrogliosis	(Donsante et al., 2016)
	Glutamine synthetase, excitatory amino acid transporter, micro RNA targeting adenosine kinase (miADK)	Temporal lobe epilepsy	Astrocytes		Kainate-treated SD rats	miADK reduced seizure duration	(Young et al., 2014)
	β-galactosidase	GM1-gangliosidosis	N/S		GM1 mice	Reduced astrogliosis, improved behavior and median survival, moderate CNS expression	(Weismann et al., 2015)
AAV9 AAVrh10	GFP		Neurons, Astrocytes		B6 mice	Efficient transduction without inflammatory response	(Zhang et al., 2011)
AAVrh8 AAVhu32 AAVhu37 AAVpi2A AVhu48R3	GFP		Neurons, Astrocytes, Oligodendrocytes		C3H/HeOuJ mice	Neuronal transduction by all serotypes, astrocyte and oligodendrocyte transduction by certain serotypes	(Cearley et al., 2008)