Table 1.

Overview of experimental gene therapy for phenylketonuria using the Pah^enu2/2 mouse model

Vector System	Transgene(s)a	Promoterb	Target Organ	Injection Methodc	Documented Duration of Treatment	References
Adenovirus	hPAH	RSV-LTR	Liver	i.p	1 week	Fang et al.42
	hPAH	CAG	Liver	i.p or i.v.	11 days	Nagasaki et al.43
rAAV2/2	hPAH	EF	Liver	i.p	Up to 25 weeks	Oh et al.44
rAAV2/5	mPah	CBA	Liver	i.p	Up to 40 weeks	Mochizuki et al.45
rAAV2/8	mPah	CBA	Liver	i.v. or i.p.	Up to 42 weeks	Ding et al.49
rAAV2/8	mPah	LPS	Liver	i.p.	Up to 17 weeks	Harding et al.48
rAAV2/1	Pah, Gch1, Pts	CMV	Muscle	i.m	Up to 70 weeks	Ding et al.55
rAAV2/1, rAAV2/2, rAAV2/8	mPah	CBA	Liver	i.m.	Up to 53 weeks	Rebuffat et al.52
scAAV2/8	mPah	LP1	Liver	i.p.	Up to 52 weeks	Yagi et al.50
Naked DNA (minicircle)	mPah	P3	Liver	HTV	Up to 52 weeks	Viecelli et al.57
	mcoPah	P3, endogenous	Liver	HTV	Up to 60 weeks	Grisch-Chan et al.62
rAAV2/8 intein	APOBEC-nSaCas9 sgRNA	P3, U6	Liver	i.v.	Up to 26 weeks	Villiger et al.80
AAVHSC15	hPAH	Endogenous	Liver	i.v.	Up to 8 weeks	Wright et al.54

Note that all Pah^enu2/2 mice were treated as adults.

^ahPAH, human Pah gene; mPah, murine Pah gene; mcoPah, murine, codon-optimized Pah gene; Gch1, guanosine triphosphate cyclohydrolase I; Pts, 6-pyruvoyltetraphydrobiopterin synthase.

^bRSV-LTR, Rous sarcoma virus long-terminal repeat; CBA, CMV (cytomegalovirus) early enhancer/chicken β actin promoter; EF, human elongation factor 1-α promoter; CMV, cytomegalovirus promoter; LPS; liver-specific promoter is a combination of two copies of a human a1-microglobulin/bikunin enhancer and the promoter from the human thyroid hormone-binding globulin gene⁴⁸; LP1 promoter consists of the human apolipoprotein E/C-I hepatic control region and the human α1-antitrypsin promoter⁵⁰; P3, synthetic liver-specific promoter⁶¹; U6, RNA polymerase III promoter.

^ci,p., intraportal vein infusion; i.v., intravenous tail vein infusion; i.m., intramuscular (M. gastrognemius); i.p, intraperitoneal injection; HTV, hydrodynamic tail vein injection.