TABLE 2.

Preclinical studies of genome editing for CNS pathologies.

Editing approach	Disease	Gene	Model	Editing tool	Delivery	Selectivity	Target efficiency (indels/expression)	Behavioral improvements	Publication
NHEJ	MECP2 duplication syndrome	Mecp2	MECP2-TG mouse	SpCas9	AAV-split system	Non-selective	50% reduction MECP2 protein	Improvements in social recognition	Yu et al., 2020
	Fragile X syndrome	mGluR5	Fmr1 knockout mouse	SpCas9	CRISPR-Gold RNP complexes	Non-selective	14.6% indels 40–50% reduction mGluR5 mRNA and protein	Rescued the excessive digging and repetitive jumping	Lee B. et al., 2018
	Alzheimer’s disease	Bace1	5XFAD and APP-KI mouse	SpCas9	Amphiphilic RNP complexes	Non-selective	45% indels 34% reduction Bace1 mRNA	Behavioral improvements	Park et al., 2019
		APP	WT mouse	SpCas9	AAV9-split system	Non-selective	50% reduction full-lenght APP protein	No data	Sun et al., 2019
		APP-SW	Tg2576 mouse	SpCas9	AAV9-split system	Mismatch-based	1.3% indels (APPsw alleles)	No data	György et al., 2018
	DFNA36 (hearing loss)	Tmc1	Beethoven mouse (Bth/wt)	SpCas9	Cationic lipid-mediated RNP complexes	Mismatch-based	1.8% indels (mutant alleles)	Protection of the acoustic behavioral reflexes	Gao et al., 2018
		Tmc1	Beethoven mouse (Bth/wt)	SaCas9-KKH	AAV-Anc80L65	PAM-based	2.2% indels (mutant alleles)	Stable maintenance of auditory brainstem responses	György et al., 2019
	ALS	SOD1	G93A-SOD1 mouse	SaCas9	AAV9	Non-selective	0.2–0.4% indels 65% reduction SOD1 protein	Improved survival, motor deficits and muscular strenght	Gaj et al., 2017
	Huntington’s disease	HTT	HD140Q-KI mouse	SpCas9	AAV-split system	Non-selective	10–80% reduction HTT protein	Improved motor deficits	Yang et al., 2017
		HTT	BacHD mouse	SpCas9	AAV1-split system	PAM-based	50% reduction mHTT mRNA	No data	Monteys et al., 2017
		HTT	LV-hHTT-82Q mouse	SpCas9 (self-inactivating)	LV-split system	Non-selective	30% HTT indels (exogenous)	No data	Merienne et al., 2017
	LCA10	CEP290	CEP290 IVS26-KI mouse and monkeys	SaCas9	AAV5	Non-selective	21.4% and 27.9% indels	No data	Maeder et al., 2019
HDR	Sandhoff and Tay–Sachs diseases	ALB	Sandhoff mouse	SaCas9 + dsTemplate-HEXM	AAV8	Non-selective	144- and 17-fold increase MUGS and MUG activities (indirect)	Improved motor deficits (totarod test)	Ou et al., 2020
	Retinitis pigmentosa	Pde6b	Rodless (rd1) mouse	SpCas9 + RecA-MS2 + sgRNA-MS2 loops + ssTemplate	Plasmid electroporation	Non-selective	2% gene correction	Partial rescue of the pupillary light reflexes	Cai et al., 2019
Base editing	DFNB7/B11 (hearing loss)	Tmc1	Tmc1 (Y182C/Y182C) mouse	SpCas9-based AID-BE4max	AAV-Anc80L65-split system	Non-selective	2.3% gene correction	Improved auditory brainstem responses	Yeh et al., 2020
Transcriptional activation	Parkinson’s disease	GDNF	6-OHDA rat	GDNF-6ZF-p65	AAV2	Non-selective	60% increase GDNF mRNA	Rescued motor deficits	Laganiere et al., 2010
	Alzheimer’s disease	Dlg4	AβPPswe/PS-1 mouse	PSD95-6ZF-VP64	AAV-PHP.B	Non-selective	31% increase Bace1 mRNA	Rescued memory deficits	Bustos et al., 2017
	Spinal cord injury	VEGF-A	Aneurysm clip compression rat	VEGF-3ZF-p65	Ad and AAV2	Non-selective	33% increase VEGF mRNA 55% increase VEGF protein	Improved motor deficits	Liu et al., 2010;
	Traumatic brain injury	VEGF-A	Unilateral FPI rat	VEGF-3ZF-p65	Ad and AAV2	Non-selective	25–50% increase VEGF protein	Improved motor deficits (rotarod test)	Siddiq et al., 2012
Transcriptional repression	Huntington’s disease	HTT	R6/2 mouse	mHTT-6ZF-KRAB	AAV1	CAG selective (120 repeats)	30% reduction mHTT mRNA	Improved motor deficits and clasping behavior	Garriga-Canut et al., 2012
		HTT	R6/2 and HdhQ50 mouse	mHTT-6ZF-KRAB	AAV1	CAG selective (50 repeats)	55–67% reduction mHTT mRNA	Improved clasping behavior	Zeitler et al., 2019
	Angelman syndrome	Snurf/Snrpn	Maternally Ube3a-deficient mouse	UBE3a-6ZF-KRAB	HIV TAT cell-penetrating peptide	Non-selective	20% increase UBE3A mRNA (indirect)	No data	Bailus et al., 2016