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• 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

LIVER TRANSPLANTATION Surgical Risks

Risk of Graft Loss

It is no longer 1984!

Long Term Results of Liver Transplantation 1996-2007

Data from Children’s Hospital of Pittsburgh All Etiologies of Liver Disease

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%

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

Treatment of PKU

• Phenylalanine (protein restriction)

• Close monitoring of Phe levels

• Watch for unexpected Phe sources

• Life long therapy

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!

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

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?

CELL TRANSPLANTATION

Minimally Invasive Therapy for Life-Threatening Diseases

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

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

CRIGLER-NAJJAR SYNDROME TYPE 1

HEPATOCYTE TRANSPLANTATION

HUMAN

GUNN RAT

LIVER-BASED METABOLIC DISEASE

HEPATOCYTE TRANSPLANTATION

Treatment of Children in LBMDConditioning Regimen:

Liver-Directed RT to Right Liver Lobe

(Conditioning Similar to that Required for Bone Marrow Transplantation)

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)

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

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

The Jury Is Out