1 / 19

TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE

TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE. Transplantation and PKU. Organ Transplantation Most people view transplantation as very risky, expensive, and experimental Questionable quality of life from immune suppression PKU

cortez
Download Presentation

TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE

  2. Transplantation and PKU Organ Transplantation • Most people view transplantation as very risky, expensive, and experimental • Questionable quality of life from immune suppression PKU • Most definitions of "well controlled" allow Phe levels well above normal • Approximately half of patients who use Kuvan (biopterin) respond Most do so only partially Typical adult dose is 10 pills/day at about $80,000 per year • PEG-PAL (enzyme replacement) will require weekly injections Probable adult cost: several hundred thousand dollars/year

  3. LIVER TRANSPLANTATIONSurgical RisksRisk of Graft Loss It is no longer 1984!

  4. Long Term Results of Liver Transplantation 1996-2007 Data from Children’s Hospital of Pittsburgh All Etiologies of Liver Disease

  5. Outcomes of >5 Year Survivors of Pediatric Liver Transplantation: SPLIT Pediatric Academic Multi-Organ Transplantation (PAMOT) Program Hospital for Sick Children, Toronto, Canada And EMMES Corporation, Rockville, MD, USA • Study population (N=461 Children) • 54% < 2 years old - 30% > 13 years old • (13% LBMD; 11% ALF; 4% Tumor; 47% BA) • 87% of patients still have first graft • Infection • PTLD (6%) • Growth and development • Height below 10% percentile - 29% • Weight below 10% percentile - 18%

  6. Extra-Hepatic Morbidity at the 5-Year Anniversary % of patients cGFR < 90 HTN  BMI choles triglyceride

  7. Treatment of PKU Phenylalanine (protein restriction) Close monitoring of Phe levels Watch for unexpected Phe sources Life long therapy

  8. PKU Diet Highly restrictive Socially and financially burdensome Time consuming to manage Medical and low protein foods are unpalatable to some Problems with adherence Diet for life!

  9. Consequences of Hyperphe Children Adults • When PKU is untreated: • Mental retardation or loss of IQ • Seizures • Difficulties in executive function • Psychological and behavioral issues • Social difficulties • Tremors • Irritability • Eczema • When PKU is poorly controlled: • Difficulties in executive function • Psychological and behavioral issues • Social difficulties • Neurological complications • Irritability • Eczema PKU Patients Not on Diet

  10. Maternal PKU Risk of fetal damage is extremely high in uncontrolled women (Phe > 20) 92% mental retardation 72% microcephaly 40% IUGR 12% congenital heart disease Risks are lower with lower Phe What is the critical threshold level?

  11. CELL TRANSPLANTATION Minimally Invasive Therapy for Life-Threatening Diseases

  12. HEPATOCYTE TRANSPLANTATION: LBMD CRIGLER-NAJJAR SYNDROME TYPE 1 Recessively Inherited Absence of Bilirubin-UGT Unconjugated Hyperbilirubinemia Kernicterus 30 mg/dl BILIRUBIN 0 mg/dl -30 DAYS 150 BILIRUBIN: FELL FROM 27 TO 12 MG/DL PHOTOTx: REDUCED 30-40% B-UGT ACTIVITY: 0.4 TO 5.5% NORMAL BILE: 33% BILI GLUCURONIDES

  13. HEPATOCYTE TRANSPLANTATION CRIGLER-NAJJAR SYNDROME TYPE 1

  14. HEPATOCYTE TRANSPLANTATION LIVER-BASED METABOLIC DISEASE CRIGLER-NAJJAR SYNDROME TYPE 1 GUNN RAT HUMAN

  15. HEPATOCYTE TRANSPLANTATIONTreatment of Children in LBMDConditioning Regimen: Liver-Directed RT to Right Liver Lobe(Conditioning Similar to that Required for Bone Marrow Transplantation)

  16. Regional RT Followed by Hepatocyte Transplantation Correction of Bilirubin levels in Gunn Rat model of CN-1 8- 7- 6- 5- 4- 3- 2- 1- 0- - no RT (n = 4) − HIR (ML) + Ad-HGF + HT (n=6) - RT to ML (~35% of liver; n = 6) - RT to ML + LL (~60% of liver; n-8) Serum Bilirubin Levels (mg/dl) 20 24 28 0 4 8 12 16 Time after Hepatocyte Transplantation (Weeks)

  17. RISK OF LIVER IRRADIATION IN INFANTSRT for Liver Hemangiomas - 1950s to 1980s1/3 liver can tolerate up to 10,000 Rads20 Liver Cancer Rare After Liver-Directed RTNational Wilm’s Tumor Study - 2438 patients Minimal Cancer RiskAssociated with High Dose RT and Chemotherapy

  18. PKU AND TRANSPLANTATION Liver Cell Transplantation • Providing a small percentage (5-10%) of normally functioning liver cells should provide normal PKU control with a normal diet • Sarkissian CN, et al Molec Genet and Metab 69; 188, 2000 Hamman K et al Molec Ther 12; 337, 2005 • If immune suppression becomes an issue, it can be stopped and the native liver still functions perfectly aside from the PAH defect

  19. The Jury Is Out

More Related