Safety Study of HepaStem for the Treatment of Urea Cycle Disorders (UCD) and Crigler-Najjar Syndrome (CN)

• HepaStem (Biological), also known as HHALPC,Heterologous Human Adult Liver derived Progenitor Cells

Primary outcomes

• Safety of HepaStem in paediatric patients suffering from CN or UCD [6 months]: Evaluation of the clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-HLA antibodies, and/or other immune related markers as well as Serious Adverse Events (SAEs) and clinically significant Adverse Events (AEs) related to infusion.

Secondary outcomes

• Long-term safety profile of HepaStem in both indications [From 6 to 12 months post-administration]: Assessment of reactogenicity and safety of the treatment during 6 to 12 months post infusion (long-term safety) is evaluated.
• Preliminary efficacy of HepaStem in both indications (CN and UCD) and for different weight cohorts [0-6 months, 6-12 months]: UCD: 13C tracer test to measure ureagenesis, ammonium values, amino acids in plasma, neuropsychological assessment and quality of life indicators: (1) report on actual supportive treatment and any adjustment of diet (protein restriction (low protein diet) and amino acids supplements). (2) report on cognitive skills, behaviour, and health related quality of life effect). CN: measure of the blood unconjugated bilirubin and serum total bilirubin levels and quality of life indicators: (1) adjustment of duration of phototherapy, (2) report on cognitive skills, behaviour, and (3) health related quality of life effect.

Other outcomes

• To characterize the engraftment of HepaStem [at 6 month, and optional at 12 month.]: By liver biopsy, enzymatic activity (quantitative) on the biopsies or, donor sequences by RT PCR or in situ hybridisation (FISH) or immunohistochemistry.

Sex: All, ages: any to 17 Years

GENERAL:

1. Subject shows patency of the portal vein and branches, with normal flow velocity in the main portal vein as confirmed by Doppler ultrasound and accessibility of the portal vein, or respectively, accessibility of the umbilical vein.
2. Subject (if capable of signing) and parents or legal representative have provided a written informed assent/consent.
3. Female subjects of childbearing potential need to have a negative pregnancy test and must agree to use an acceptable method of contraception throughout the study.

MAIN INCLUSION CRITERIA

Crigler-Najjar Syndrome specific:

* Patient presents with Crigler-Najjar syndrome type 1.
* Patient presents with Crigler-Najjar syndrome type 2, poorly controlled under phenobarbital treatment, or experiencing serious impairment in quality of life.

Diagnosis must be confirmed by genetic mutation analysis if not available.

Urea Cycle Disorders specific:

* Diagnosis of one of the urea cycle disorders of which the disease is of such severity to warrant liver transplantation or alternatives despite full conservative therapy,
* subject experiencing serious impairment in quality of life despite full conservative therapy.

MAIN EXCLUSION CRITERIA

* The subject is 18 years or older at time of screening.
* The subject presents acute liver failure, clinical or radiological evidence of liver fibrosis or cirrhosis, presents or has a history of hepatic or extrahepatic malignancy
* The patient has a non-corrected cardiac malformation, has a known medical or family history of coagulopathy, had or has a renal insufficiency treated by dialysis.
* The subject requires valproate therapy.
* The subject has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
* The subject has a porto systemic shunt or fistula assessed by Doppler US.
* Patients with disease of such severity that liver transplantation is an absolute indication.

• Results publication: Coppin LCF, Smets F, Ambroise J, Sokal EEM, Stephenne X. Infusion-related thrombogenesis by liver-derived mesenchymal stem cells controlled by anticoagulant drugs in 11 patients with liver-based metabolic disorders. Stem Cell Res Ther. 2020 Feb 7;11(1):51. doi: 10.1186/s13287-020-1572-7. PMID 32028991