Liver cell transplantation for Crigler-Najjar syndrome type I: Update and perspectives

Table 1 Representative liver cell transplantation experiments in the Gunn rat model

Donor cells	Injection site	Hepatic injury	Outcome	Cell tracking	References
50 × 106 free or encapsulated congeneic Hc	Peritoneum	None	34.8% serum bilirubin reduction with encapsulated Hc vs 13.5% with free Hc at 1 mo	Light and electron microscopy	22
10 × 106 syngeneic Hc	Liver	Hepatectomy	Significant reduction of serum bilirubin up to 4 wk	ND	24
			Apparition of conjugates in bile
10 × 106 congeneic Hc	Spleen	None	Significant reduction of serum bilirubin up to 12 mo	ND	27
			Apparition of bile conjugates at 4 mo
2-20 × 106 congeneic Hc	Portal vein	Right portal vein ligation	Significant reduction of serum bilirubin when injury with 2 × 106 Hc or with 20 × 106 without injury up to 30 d	UGT1A1 activity, WB, PCR for ugt1 gene	28
			Conjugates in bile after 10 d
5 × 106 congeneic Hc	Spleen	Hepatic irradiation ± Hepatectomy	Normalization of serum bilirubin only with combined injury	UGT1A1 activity, WB, IHC	29
			Conjugates in bile detected up to 5 mo
10 × 106 congeneic Hc	Spleen	Hepatic irradiation ± FasL-induced apoptosis	Normalization of serum bilirubin up to 160 d	UGT1A1 activity, WB, IHC	31
			Conjugates in bile at 150 d
			Estimation of repopulation at 52 ± 15% when combined injury
40 × 106 fetal or adult syngeneic Hc	Spleen	Retrorsine + Triiodothyronine	Significant reduction of serum bilirubin (+ conjugates in bile) up to 90 d (no difference between fetal and adult cells)	PCNA	32

Hc: Hepatocyte; IHC: Immunohistochemistry; PCNA: Proliferating cell nuclear antigen; WB: Western blot.

Table 2 Summary of clinical liver cell transplantation procedures for liver-based inborn errors of metabolism

Indication	n	Patient age	Cell amount (% liver cell mass)	Follow-up	References
Familial hypercho-lesterolemia	5	7-41 yr		Partial reduction of LDL (3/5 patients)	69
				Donor hepatocytes detected by ISH at 4 mo
CN disease type I	1	10 yr	7.5 × 109 (5%)	Decrease of bilirubin levels up to 11 mo	14
				Detection of UGT1A1 enzyme activity and of glucurono-conjugates in bile
	1	9 yr	7.5 × 109 (5%)	50%-65% reduction of bilirubin up to 3 mo	34
				Donor hepatocytes not detected by short tandem repeat analysis at 40 d
	2	18 mo/3 yr	ND	50%/30% reduction of serum bilirubin over 7 mo/ND follow-up	33
				Donor hepatocytes detected in one case by short tandem repeat analysis at 8 mo
Infantile refsum disease	1	4 yr	2 × 109	Donor Y-chromosomes detected by PCR at 7 d	20
Inherited coagulation factor VII deficiency	2	3 mo/2 yr	1.1 × 109/2.2 × 109 (4%/3%)	Decrease in the factor VII requirements	19
PFIC 2	2	ND	0.3 × 109	No improvement	33
Glycogen storage disease type Ia	1	47 yr	2 × 109(1%)	Fasting tolerance: up to 7 h	18
				Increase of glycemia
				Improvement of diet
				G6Pase activity detected
Urea cycle disease	1 (OTC)	5 yr	1 × 109	Improvement of ammonia levels	70
				Detection of enzyme activity
	1 (OTC)	0 d	10.5 × 109	Transient metabolic improvement between 20 and 31 d of life	71
	1 (OTC)	1 d	1.9 × 109	Improvement of ammonia levels	72
				Increased urea synthesis
	1 (OTC)	14 mo	2.4 × 109 (6%)	Improvement of psychomotor development and of ammonia levels	16
				Urea neo-synthesis
	1 (ASL)	3.5 yr	4.7 × 109 (9%)	Improvement of psychomotor development and of ammonia levels	17
				Donor hepatocytes detected by FISH at 12 mo and by enzyme activity at 8 mo

ASL: Arginino-succinate lyase; (F)ISH: (Fluorescent) in situ hybridization; LDL: Low density lipoproteins; ND: Not documented; OTC: Ornithine transcarbamylase; PCR: Polymerase chain reaction; PFIC: Progressive familial intrahepatic cholestasis.

Table 3 Presentation of LCT procedures in two Crigler-Najjar disease type I patients

	Patient 1	Patient 2
Age/Gender	9 yr/Female	1 yr/Female
Infusion procedure	Porth-a-cath in jejunal vein	Broviac in portal vein
Timing of infusions	18 infusions/5 mo	14 infusions/15 d
Donor cells	Fresh and cryopreserved from 3 donors	Fresh and cryopreserved from 1 donor
Cell amount	6.1 billion	2.6 billion
	0.16 billion/kg	0.35 billion/kg
% Liver cell mass	4%	8%
Mean viability	80%	83%