Table 1.

Summary of selected ongoing initiatives which have been available in recent years for different CNS disorders approached by with AAV-based therapeutics, such as Alzheimer disease (AD), Huntington disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA), as well as either vision- or hearing-related diseases. Abbreviations: Aβ (β-amyloid), APOE (apolipoprotein E), shIRS1 (short hairpin RNA against insulin receptor substrate 1), NTR (neurotrophin receptor), CCL2 (chemokine L2), ECE (endothelin-converting enzyme), NGF (nerve growth factor), scFv (semisynthetic anti-Aβ antibody), PHF1 (monoclonar antibody against TAU), IL-10 (interleukin-10), BDNF (brain-derived neurotrophic factor), GDNF (glial cell-derived neurotrophic factor), HTT (huntingtin protein), SIRT3 (mitochondrial protein deacetylase), XBP1 (X-box binding protein 1), ZNF10 (zinc finger protein 10), SREBP2 (sterol regulatory element-binding protein 2), AAT (α-1 antitrypsin), SOD1 (superoxide dismutase 1), HGF (hepatocyte growth factor), hIGF1 (insulin-like growth factor 1), DOK7 (tyrosine kinase 7), GLT1 (glutamate transporter 1), NMJ (neuromuscular junction), TGF-β1 (transforming growth factor beta 1), CAD180 (calreticulin anti-angiogenic domain), SYNE4 (spectrin repeat containing nuclear envelope family member 4), XIAP (X-linked inhibitor of apoptosis).

Disease	Delivery Routes	Target	Species	AAV Serotype	References
Alzheimer	Intraparenchymal	Aβ	Mice	AAV1	[12]
	Intraparenchymal	APOE2	Mice	AAV9 and AArh10	[13]
	Intraparenchymal	shIRS1 (IRS1: neuroprotective role)	Rats	AAV2/DJ8	[14]
	Intraparenchymal	CCL2 (diffuse amyloid plaques)	Mice	AAV1/2	[15]
	Intraparenchymal	ECE (protease involved in Aβ degradation)	Mice	AAV5	[16]
	Intraparenchymal	NGF (improving cholinergic activity)	Rats	AAV2 and AAV5	[17]
	Intraparenchymal	NGF	Mice	CERE-110 (AAV2)	[18]
	Intraparenchymal	PHF1 (anti-phospho-TAU antibody)	Mice	AAVrh10	[19]
	Intraparenchymal	CascFv59 (anti-Aβ antibody)	Mice	AAV2	[20]
	Intraparenchymal	IL-10 (inhibition of proinflammatory cytokines)	Mice	AAV1	[21]
	Intramuscular and intravenous	GFP	Mice	AAV9, exo-AAV9 (IM) and AAV8 (IV)	[22]
	Intramuscular	scFv (anti-Aβ antibody)	Mice	AAV1	[23]
	Intramuscular	P75NTR (protective against Aβ)	Mice	AAV8	[24]
	Intracerebroventricular	GFP	Mice	AAV1, AAV5, AAV8, AAV9, AAV2-BR1 and AAV2-PHP.eB	[25]
Huntington	Intraparenchymal	82Q (mutant Htt)	Rats	AAV2	[26]
	Intraparenchymal	BDNF and GDNF	Rats	AAV2	[27]
	Intraparenchymal	CRISPR/Cas9 (Htt)	Mice	AAV1	[28]
	Intraparenchymal	SIRT3 (protective against oxidative and mitochondrial stress)	Mice	AAV-DJ	[29]
	Intraparenchymal	XBP1 (involved in the splicing events of Htt)	Mice	AAV2	[30]
	Intraparenchymal	mRNA or siRNA (Htt)	Mice	AAV9	[31]
	Intraparenchymal	iRNA (Htt)	Mice	AAV8	[32]
	Intraparenchymal	Exon1-Q138 mHtt and Exon1-Q17 wildtype Htt	Mice	AAV9	[33]
	Intraparenchymal	Human KRAB domain from KOX1 (ZNF10); ZNF10 represses mutant Htt expression	Mice	AAV9	[34]
	Intraparenchymal	GFP	Rats	AAV1, AAV2 and AAV5	[35]
	Intraparenchymal	GDNF (neurturin)	Mice	AAV8	[36]
	Intraparenchymal	miHDS1 (Htt)	Mice	AAV1	[37]
	Intraparenchymal	SREBP2 (to reverse synaptic defects in Huntington disease)	Mice	AAV5	[38]
	Intraparenchymal	siRNA (Htt)	Sheep	AAV serotype not disclosed	[39]
	Intravenous	iRNA (Htt)	Mice	AAV1	[40]
	Intramuscular and intravenous	shRNA (AAT)	Mice	AAV8 (IV) and AAV6 (IM)	[41]
	Intrathecal	miRNA based on endogenous mir155 backbone (Htt)	Sheep	AAV9	[42]
Amyotrophic lateral sclerosis	Intraparenchymal and intramuscular	GFP	Mice	AAV1, AAV2, AAV5, AAV6, AAV7, AAV8	[43]
	Intravenous and intracisternal	SOD1	Mice	AAVrh10	[44]
	Intravenous	IGF1	Mice	AAV9	[45]
	Intravenous	GDNF	Rat	AAV9	[46]
	Intracerebroventricular	GFP	Mice	AAV9	[47]
	Intramuscular	HGF in SOD1 model	Mice	AAV6	[48]
	Intramuscular	hIGF1 in SOD1model	Mice	AAV9	[49]
	Intramuscular	GDNF	Mice	AAV2	[50]
	Intramuscular	GDNF	Mice	AAV2	[51]
	Intramuscular	GFP	Mice	AAV1, AAV5, AAV8 and AAV9	[52]
	Intramuscular	SOD1	Mice	AAV6	[53]
	Intramuscular	IGF1 and GDNF	Mice	AAV2	[54]
	Intramuscular	IGF1	Mice	AAV9	[55]
	Intrathecal	GLT1 overexpression in SOD1 animal model	Mice	AAV8	[56]
	Intrathecal	SOD1	Mice	AAV9	[57]
	Intracisternal	C9orf72 hexanucleotide repeat expansions (generates neuropathology)	Mice	AAV9	[58]
Spinal muscular atrophy	Intracerebroventricular and intraperitoneal	GFP	Mice	AAV9	[59]
	Intracerebroventricular	SMN1 (gene replacement strategy)	Mice	AAV9	[60]
	Intracerebroventricular (mice) and intracisternal (pigs and NHP)	hSMN1	Mice, Pigs, and NHPs	AAV9	[61]
	Intracerebroventricular and intravenous	SMN1	Mice	AAV9	[62]
	Intramuscular	DOK7 (tuning down disease severity)	Mice	AAV9	[63]
	Intravenous	SMN transgene	Piglets and NHPs	AAVhu68	[64]
	Intramuscular	GFP	Mice	AAV9	[65]
	Intrathecal	SMN2 (to rescue the SMA model)	Mice	AAV9	[66]
	Intracisternal	miRNA	Mice	AAVrh10	[67]
Vision disorders	Subconjuntival	GFP	Mice	AAV2, AAV6 and AAV8	[68]
	Intravenous	CRISPR/Cas9 (retinitis pigmentosa)	Mice	AAV2, AAV6 and AAV8	[69]
	Subretinal	TGF-β1 (retinitis pigmentosa)	Mice	AAV8	[70]
		GFP	Mice and NHPs	AAV7m8 and AAV8BP2	[71]
		GFP	Mice	AAV8, AAV9. AAV-PHP.B, AAV-PHP.eB	[72]
		GFP	Mice and pigs	AAV8	[73]
	Retinal	CRISPR/Cas9 (retinal editing)	Mice	AAV2 and AAV7	[74]
	Intravitreal	CAD180 (endogenous inhibitor of angiogenesis) retinal neovascularization (RNV)	Mice	AAV2	[75]
		GFP	NHPs	AAV2	[76]
		GFP	Mice and NHPs	AAV2	[77]
		GFP	Mice	AAV2, AAV5, AAV8 and AAV9	[78]
Hearing disorders	Cochlear	CRISPR/Cas9 (gene editing)	Mice	AAV2	[79]
		SYNE4 (to rescue in a deafness model)	Mice	AAV9-PHP.B	[80]
		GFP	Mice	AAV2, AAV6, AAV8, AAV/Anc80L65	[81]
		GFP	Mice and guinea pigs	AAV2, AAV9 and Anc80L65	[82]
	Canalastomy (inner ear cells)	GFP	Mice	AAV1, AAV2, AAV6.2, AAV8, AAV9, AAVrh.39, AAVrh.43 and Anc80L65	[83]
		CRISPR/Cas9 (GFP, Biodistribution)	Mice	AAV8	[84]
	Round window membrane	XIAP against Cisplatin (chemotherapeutic agent)	Mice	AAV2	[85]
		GFP	Mice and NHPs	AAV9-PHP.B	[86]
		Harmonin-a1 and harmonin-b1 (To rescue Usher syndrome type 1c)	Mice	AAV1 and AAV/Anc80L65	[87]
		GFP	Mice	AAV1 and exo-AAV1	[88]
		GFP	Mice	AAV2/DJ, AAV2/DJ8, AAV2-PHP.B	[89]
	Utricle (inner and outer cells)	GFP	Mice	AAV9-PHP-B, Anc80L65 and AAV2.7m8	[90]