TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE
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Transcript of TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE
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TRANSPLANTATION OF ISOLATED LIVER CELLS
IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE
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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 injectionsProbable adult cost: several hundred thousand dollars/year
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LIVER TRANSPLANTATION Surgical Risks
Risk of Graft Loss
It is no longer 1984!
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Long Term Results of Liver Transplantation 1996-2007
Data from Children’s Hospital of Pittsburgh All Etiologies of Liver Disease
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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
• InfectionPTLD (6%)
• Growth and developmentHeight below 10% percentile - 29%
Weight below 10% percentile - 18%
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Extra-Hepatic Morbidity Extra-Hepatic Morbidity at the 5-Year Anniversaryat the 5-Year Anniversary
0
10
20
30
40
50
% o
f p
atie
nts
cGFR < 90 HTN BMI choles triglyceride
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Treatment of PKU
• Phenylalanine (protein restriction)
• Close monitoring of Phe levels
• Watch for unexpected Phe sources
• Life long therapy
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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!
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Consequences of Hyperphe
When PKU is untreated: Mental retardation or loss of IQ Seizures Difficulties in executive function Psychological and behavioral
issues Social difficulties Tremors Irritability Eczema
Children
When PKU is poorly controlled: • Difficulties in executive function Psychological and behavioral
issues Social difficulties Neurological complications Irritability Eczema
Adults
PKU Patients Not on Diet
PKU Patients Not on Diet
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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?
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CELL TRANSPLANTATION
Minimally Invasive Therapy for Life-Threatening Diseases
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CRIGLER-NAJJAR SYNDROME TYPE 1HEPATOCYTE TRANSPLANTATION: LBMD
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
Recessively InheritedAbsence of Bilirubin-UGT
Unconjugated HyperbilirubinemiaKernicterus
BILIRUBIN
30 mg/dl
0 mg/dl
DAYS 150-30
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HEPATOCYTE TRANSPLANTATIONCRIGLER-NAJJAR SYNDROME TYPE 1
-7 93 193 295 395 495 595 6950
5
10
15
20
25
30
Bilir
ub
in (
mg
/dl)
days
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CRIGLER-NAJJAR SYNDROME TYPE 1
HEPATOCYTE TRANSPLANTATION
HUMAN
GUNN RAT
LIVER-BASED METABOLIC DISEASE
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HEPATOCYTE TRANSPLANTATION
Treatment of Children in LBMDConditioning Regimen:
Liver-Directed RT to Right Liver Lobe
(Conditioning Similar to that Required for Bone Marrow Transplantation)
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8-
7-
6-
5-
4-
3-
2-
1-
0-0 4 8 12 16
Seru
m B
iliru
bin
Leve
ls (m
g/dl
)
Time after Hepatocyte Transplantation (Weeks)20 24 28
Regional RT Followed by Hepatocyte Transplantation Correction of Bilirubin levels in Gunn Rat model of CN-1
- RT to ML + LL (~60% of liver; n-8)- RT to ML + LL (~60% of liver; n-8)
- no RT (n = 4)- no RT (n = 4)
- RT to ML (~35% of liver; n = 6)- RT to ML (~35% of liver; n = 6)
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RISK OF LIVER IRRADIATION IN INFANTS
RT for Liver Hemangiomas - 1950s to 1980s
1/3 liver can tolerate up to 10,000 Rads
20 Liver Cancer Rare After Liver-Directed RT
National Wilm’s Tumor Study - 2438 patients
Minimal Cancer Risk Associated with High Dose RT and Chemotherapy
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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
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The Jury Is Out