Clinical Outcome of Hepatocyte Transplantation in Four Pediatric Patients with Inherited Metabolic Diseases

Abstract

Hepatocyte transplantation (HT) has become an effective therapy for patients with metabolic inborn errors. We report the clinical outcome of four children with metabolic inborn errors that underwent HT, describing the cell infusion protocol and the metabolic outcome of transplanted patients. Cryopreserved hepatocytes were used as this allows scheduling of treatments. Functional competence (viability, cell attachment, major cytochrome P450 and UDP-glucuronosyltransferase 1A1 activities, and urea synthesis) and microbiological safety of cell batches were assessed prior to clinical use. Four pediatric patients with liver metabolic diseases [ornithine trans carbamylase (OTC) deficiency, Crigler-Najjar (CNI) syndrome, glycogen storage disease Ia (GSD-Ia), and tyrosinemia type I (TYR-I)] underwent HT. Indication for HT was based on severity of disease, deterioration of quality of life, and benefits for the patients, with the ultimate goal to improve their clinical status whenever liver transplantation (LT) was not indicated or to bridge LT. Cells were infused into the portal vein while monitoring portal flow. The protocol included antibiotic prophylaxis and immunosuppressant therapy. After HT, analytical data on the disease were obtained. The OTC-deficient patient showed a sustained decrease in plasma ammonia levels and increased urea production after HT. Further cell infusions could not be administered given a fatal nosocomial fungus sepsis 2 weeks after the last HT. The CNI and GSD-Ia patients improved their clinical status after HT. They displayed reduced serum bilirubin levels (by ca. 50%) and absence of hypoglycaemic episodes, respectively. In both cases, the HT contributed to stabilize their clinical status as LT was not indicated. In the infant with TYR-I, HT stabilized temporarily the biochemical parameters, resulting in the amelioration of his clinical status while diagnosis of the disease was unequivocally confirmed by full gene sequencing. In this patient, HT served as a bridge therapy to LT.

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics

“…Pilot studies of hepatocyte transplantation have demonstrated persistence of donor cells, although the long-term efficacy of this approach remains to be demonstrated 186,187 Efficacy from liver-targeted gene therapy in GSD Ia might be expected, given the experience with human patients after liver transplantation. Adeno-associated virus (AAV) vectors containing a human G6Pase regulatory cassette/promoter have proven to be efficacious in animal models of GSD Ia, and these vectors contain sequence elements that regulate G6Pase expression appropriately.…”

Chemokine-Mediated Robust Augmentation of Liver Engraftment: A Novel Approach

“…Despite clinical improvements in patients, significant problems have arisen because of inefficient engraftment, death or ectopic distribution of cells that did not engraft in the target tissue, emboli formation, immunological rejection, and transient effects of transplanted cells [34][35][36]. A number of preconditioning regimens including irradiation or chemicals have been tried but discontinued for various reasons such as senescence, radiation hazards, or an increased risk of cancer [37,38].…”

Human Hepatocyte Transplantation in Patients with Hepatic Failure Awaiting a Graft

“…Cells were assessed for viability, attachment to collagen-coated plates, drug-metabolizing activities (CYP3A4, CYP2C9, CYP2E1, CYP2A6 and CYP1A2), UDP-glucuronosyltransferase 1A1 and urea formation from ammonia as previously described [18,21]. …”

“…Human hepatocytes were prepared from livers rejected for LT and freshly isolated hepatocytes were cryopreserved in University of Wisconsin solution containing 10% dimethyl sulfoxide as described previously in detail [18]. …”

“…In addition, the results obtained with artificial liver support systems (MARS: molecular adsorbent recirculating system) are inconclusive [4,5]. Hepatocyte transplantation (HT) is a promising treatment to temporarily support liver function in patients until an organ becomes available for LT or to facilitate liver regeneration in cases of acute liver failure [6,7,8,9,10,11,12,13,14,15,16,17,18]. …”