Gene Regulation Systems for Gene Therapy Applications in the Central Nervous System

Table 1

Summary of use of gene regulation systems for in vivo CNS applications.

Regulation system (VC*)	Stimuli/dose	Delivery vehicle	Species	Transgene	Comments [ref]
Tet-Off (VC1)	Dox (300 μg/mL and 2 mg/mL)	AAV	Rat	GFP	Some leakiness. No further transgene repression by increasing dox dosage [4].
Tet-On (VC2)	Dox (6 g/kg)	AAV	Rat	EGFP	No repression or basal expression data [5].
Tet-On (VC1 & 2)	Dox (2 mg/mL)	Ad	Rat	LacZ	Negligible expression following dox removal [6].
Tet-Off (VC1)	Dox	AAV	Rat	GDNF	Undetectable transgene levels at serum dox levels below those required for antimicrobial activity [7].
Tet-Off (VC2)	Dox (300 μg/mL)	AAV	Rat	EGFP	Low basal expression with addition of insulator sequences [9].
Tet-On (VC2)	Dox (600 μg/mL)	AAV	Rat	GDNF	Some basal expression [11].
Tet-Off (VC3)	Dox (2 mg/mL)	Ad	Rat	Caspase-9 & EGFP	Variable repression achieved; transgene dependent [13].
Tet-On (VC1)	Dox (2 mg/mL)	LV	Rat	Luciferase	Low basal expression [19].
Rapamycin	Rapamycin (10 mg/kg)	AAV	Rat	hAADC	Robust phenotypic response in 6-OHDA model. Low basal expression without phenotypic effect [25].
Rapamycin	AP21967 (1 mL/kg)	LV	Mouse	GFP & GDNF	No basal expression [28].
RU486	RU486 (25 mg/kg)	HSV	Rat	LacZ	Very low basal expression [31].
HRE	30 min hypoxia in a 3% O2 hypoxic chamber	Ad	Mouse	Luciferase	No transgene expression under normoxic conditions [36].
HRE	60 min MCAO	Ad	Mouse	BDNF & EGFP	Neuroprotection & phenotypic changes seen. No comparison with unregulated transgene expression [37].
HRE	45 min MCAO	AAV	Mouse	VEGF or LacZ	Angiogenesis seen. No transgene expression under nonischemic conditions [39].
HRE	Spinal cord contusion injury	Naked plasmid injection	Rat	VEGF	Locomotor recovery compared to uninjected controls [42].
HRE	Spinal cord contusion injury	Naked plasmid injection	Rat	Luciferase	Higher transgene expression in injured compared to normal spinal cord [44].
HRE	Spinal cord contusion injury	Ex vivo stem cell therapy	Rat	Luciferase	Low transgene expression in normal spinal cord [45].

*VC, Vector Configuration (see Figure 2); Dox, doxycycline; GFP, Green Fluorescent Protein; EGFP, Enhanced Green Fluorescent Protein.