Download Enzyme Replacement Therapy

Interventional
Genetics
Greg Enns, MB, ChB
Professor of Pediatrics
Director, Biochemical Genetics Program
Lucile Packard Children’s Hospital
Stanford University
October 27, 2015
1
Learning Objectives
• Understand the rationale underlying acute and chronic
therapy for metabolic disorders
• Describe the potential benefits and pitfalls of different
methods used for treating lysosomal disorders
• Understand the roles of hematopoietic stem cell
transplantation and solid organ transplantation in treating
inborn errors of metabolism
2
Interventional Genetics
• Dietary restrictions
• Enzyme replacement therapy (ERT)
• Medical foods
• Substrate reduction therapy (SRT)
• Co-factor therapy
• Redox modulation therapy (RMT)
• Alternative pathway therapy
• Chaperone therapy
• Bone marrow transplantation
• Gene therapy
• Organ transplantation
• Stem cell transplantation
3
Urea Cycle Disorders
Survival Without Alternative Pathway Medications
• 217 patients (1972-2000)
• 121 patients with neonatal onset disease
– 84% mortality (60% excluding OTC males)
• 96 patients with late-onset forms
– Present at any age
– 28% mortality
– Risk of disability
Nassogne et al. JIMD 2005;28:407-14
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“Ammonia-Scavenging” Medications
BENZOATE
COOGLUTAMINE
PHENYLACETATE
CH2-COO-
CoA
CoA
GLYCINE
Benzoyl-CoA
Phenylacetyl-CoA
CO-NH-CH2-COO-
CH2-CO-NH-CH-(CH2)2-CONH2
COO+ CoA
CoA +
HIPPURATE
PHENYLACETYLGLUTAMINE
Urea Cycle Patient Survival
Alternative Pathway Therapy
Enns et al. N Engl J Med 2007;356:2282-92
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Urea Cycle Patient Survival
Alternative Pathway Therapy
Enns et al. N Engl J Med 2007;356:2282-92
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Neurologic Outcome
• 24 children, ages 12 to 74 months
• Alternative pathway therapy
• 92% 1-yr survival
• Mean IQ 43 ± 6, 21% IQ >70
• 79% ≥1 developmental disability
• Stage III or IV coma correlates with IQ
• Peak ammonium (351 - 1800 M) does not correlate with IQ
Msall et al. N Engl J Med 1984;310:1500-5
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Liver Transplantation in
Urea Cycle Disorders
• Wordwide data
• >50 transplantations
• Survival >90% at 5 years
• Surviving patients with “satisfactory” QOL
• Use of heterozygous carriers acceptable
• Definitive treatment for UCDs
Liver Transplant 2005;11:1332-42
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Liver Transplantation in
Urea Cycle Disorders
Liver Transplant 2005;11:1332-4210
Urea Cycle Defect Transplantation
Lucile Packard Children’s Hospital 2001-2012
• 23 patients (12 F, 7 M)
– CPS (n=5), AL (n=6), AS (n=4), OTC (n=8, including 4 F)
– 14 with neonatal presentation
– Mean age 3.4 years at transplantation
– 15 whole liver graft, 7 reduced-size graft, 1 living donor
• Mean follow-up of 5 years
– 100% survival, 96% graft survival
• 11 patients had psychomotor delay before transplantation and this
remained stable or improved post-tx
Kim et al. Pediatr Transpl 17:158-167, 2013
OTC Deficiency
• DOL 2
• Lethargy, poor feeding
• NH3 ~3000 M
• HD/CVVH
• Liver Tx 3 months
• Developmental delay
– Motor 9 months
– Speech
•
•
Expressive 9 – 12 months
Receptive normal
– Cognitive
•
Age 18 months
10 months (assessed at 12 months)
OTC Deficiency
•
•
•
•
•
34 weeks of gestation
History of neonatal loss (OTC deficiency)
DNA analysis → amniocentesis
Prenatal treatment with IV sodium benzoate + sodium phenylacetate
Immediate placement of central line postpartum → continuous NaBZ
+ NaPA
• Maximal plasma ammonium <80 umol/L
• Transplanted at age 3 months
• Normal development at age 2 years
http://med.stanford.edu/ism/2010/april/enns-0426.html
Liver Transplantation in Maple Syrup Urine
Disease
Am J Transplant 2006;6:557-64
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14 MMA patients
LT (n=6)
LKT (n=8)
No further metabolic crises
Stabilization of neurocognitive
development
Need for KT later in life?
J Pediatr 166(6):1455-61, 2015
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Hepatocyte Transplantation
• Infant male OTC deficiency
• Alternative pathway therapy started
at birth
• Hemodialysis for ammonium of 146 M
• Hepatocyte infusion at 10 hours; repeated over
several weeks
• Liver transplantation at 6 months
Horslen et al. Pediatrics 2003;111:1262-7
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Transplanted Hepatocytes Were Infused
Via a Catheter Placed in the Umbilical Vein
Copyright ©2003 American Academy of Pediatrics
Horslen et al. Pediatrics 2003;111:1262-1267
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Cell-Based Therapies for Metabolic
Liver Disease
• Partial correction of underlying metabolic defect
• Lack of sustained benefit
– Inadequate cell dose
– Variations in quality of hepatocyte preparations
– Rejection of transplanted cells
– Senescence of transplanted cells
• The future?
– Stem cells
– Progenitor cells
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ENZYME REPLACEMENT THERAPY
“From Cytases to Lysosomes”
Lysosomal dysfunction related to “cellular
dyspepsia” secondary to a deficient enzyme
De Duve C. Fed Proc 1964;23:1045
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ENZYME REPLACEMENT THERAPY
“Both in our pathogenic speculations and in our
therapeutic attempts, it may be well to keep in
mind that any substance which is taken up
intracellularly by an endocytic process is likely
to end up within lysosomes.”
De Duve C. Fed Proc 1964;23:1045
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ENZYME REPLACEMENT THERAPY
“This obviously opens up many possibilities for
interaction, including replacement therapy.”
De Duve C. Fed Proc 1964;23:1045
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ENZYME REPLACEMENT THERAPY
The replacement of a defective enzyme with a
normal genetically engineered enzyme (tagged
with a specific cellular recognition signal) by
intermittent intravenous infusion.
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Nature Reviews Genetics 3:954,2002
Mannose-6 phosphate receptor
mediated uptake to lysosomes
24
Enzyme Replacement Therapy
• Intermittent infusion of genetically engineered
enzyme
• Bone marrow transplantation
• Gene therapy
• Stem cell therapy
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Lysosomal Storage Disorders
CNS Involvement
Significant or severe CNS involvement
(~ 54%)
Mucolipidosis type II / III
2%
Sandhoff
GM 1
2%
Niemann-Pick A
Gangliosidosis
Other
2%
2%
2%
Niemann-Pick C
4%
Sanfilippo B
4%
Tay-Sachs
4%
No or minimal CNS involvement
(~ 46%)
Gaucher type I
13%
Scheie (MPS I)
1%
Hurler/Scheie (MPS I)
4%
Fabry
7%
Hunter Mild
1%
Pompe
5%
Krabbe
6%
Hunter Severe
5%
Sanfilippo A
7%
Metachromatic
Leukodystrophy
8%
Adapted from Meikle P et al. JAMA. 1999;281:249-254.
Morquio
5%
Cystinosis
4%
Sanfilippo D
1%
Maroteaux-Lamy
Hurler (MPS I)
3%
Niemann-Pick
B
Mannosidosis
1%
4%
2%
Gaucher type 2 & 3
1%
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BLOOD-BRAIN BARRIER
• Cerebral microvasculature protects the brain from bloodborne toxins
• Endothelial cells use specific transporters
• Effective barrier v. therapeutic drugs and enzymes
• Major problem for ERT in diseases that affect CNS
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Type 1 Gaucher
Hepatosplenomegaly
Signs &
Symptoms
Bone pathology
Erlenmeyer flask deformity1
1. Wenstrup RJ et al. Br J Radiol. 2002;75(suppl 1):A2-A12.
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Type 1 Gaucher
Asymptomatic
80-year-old man
Clinical
Heterogeneity
Mildly affected
young adult
Severely affected
girl
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Type 1 Gaucher
Treatment
Strategies
ERT: Imiglucerase
• Produced by recombinant DNA technology
• Addresses underlying enzyme deficiency
• Administered by intravenous infusion every 2 weeks
• Reduces or reverses hepatosplenomegaly1
• Improves anemia and thrombocytopenia1
• Reduces incidence of bone pain or bone crisis1
1. Weinreb NJ et al. Am J Med. 2002;113:112-119.
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MPS I
Treatment
Strategies
Supportive care
• Physical therapy, CPAP, hearing aids, surgery
• Does not address enzyme deficiency
Hematopoietic stem cell transplantation (HSCT)
• Bone marrow, umbilical cord, or peripheral blood
• Best outcomes are in severe MPS I (<2 y)1-3
• Morbidity and mortality
Enzyme replacement therapy (ERT)
• Not shown to impact central nervous system
1. Vellodi A et al. Arch Dis Child. 1997;76:92.
2. Whitley C et al. Am J Med Genet. 1993;46:209-218.
3. Peters C et al. Blood. 1998;91:2601-2608.
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MPS I
Patient Case
• 9 months: Parents notice she “looks different” than other children.
Hepatomegaly and kyphosis noted on exam. PMD contacted
biochemical genetics.
• dermatan and heparan sulfate in urine
• Absent -iduronidase activity
• Mild corneal opacity, mild valvular disease, normal spine, Jshaped sella
• Referred to BMT
Courtesy Humboldt Radiology, Eureka, CA.
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MPS I
Treatment
Strategies
ERT: Laronidase
• Indicated for Hurler and Hurler-Scheie forms of MPS I
and for moderate to severe Scheie form
• Risks/benefits of treating mild Scheie form have not
been established
• Shown to improve pulmonary function and walking capacity
• Hepatomegaly, urine glycosaminoglycans
• Improve sleep apnea and shoulder flexion in severe patients
• Not evaluated for effects on CNS
• Intrathecal therapy in clinical trials
Wraith et al. J Pediatr 2004;144:581-8.
33
MPS I
Treatment
Strategies
laronidase adverse events
Most
common
Most common
requiring intervention
Upper respiratory tract infection
Infusion-related hypersensitivity
reactions, including:
• Flushing
• Fever
• Headache
• Rash
Rash
Injection site reaction
Most serious
Anaphylaxis
Most infusion-related reactions requiring intervention improved with:
• Slowing of the infusion rate
• Temporarily stopping the infusion and/or
• Administering additional antipyretics and/or antihistamines or steroids
34
Bone Marrow Transplantation
Treatment
Strategies
• HSCT is the preferred therapy
for MPS I patients <2.5 years
old
• All patients, whether or not
they have been transplanted,
may benefit from ERT
• ERT should be started at
diagnosis and may be of value
while waiting for transplantation
Orphanet J Rare Dis 2011;6:55.
35
Bone Marrow Transplantation
Treatment
Strategies
• Donor-derived microglia
• Bone and CNS relatively resistant
• Significant risk of morbidity/mortality
– MPS I
Krabbe disease
– MPS II
Metachromatic leukodystrophy
– MPS III
Niemann-Pick disease
– MPS VI
α-Mannosidosis
– MPS VII
Fucosidosis
Kaye Curr Treat Options Neurol 2001;3:249-56.
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Lysosomal Acid Lipase (LAL) Deficiency
Biology
LAL – hydrolyzes cholesteryl esters in lysosomes
Failure of normal hydrolysis leads to cellular accumulation of
triglycerides and cholesteryl esters
If LAL activity <5% of normal the rate of late
endosomal/lysosomal release of cholesterol falls to below
a critical level
• Aberrant regulation of ATP-binding cassette transporter
A1 (ABCA1)
• Decreased loading of phospholipids and cholesterolto
apolipoprotein A-1
Bowden et al., 2011
• Decreased HDL
Reynolds, 2013
LAL Deficiency in Children and
Adults
Signs and
Symptoms
Prominent hepatic manifestations
•
•
•
•
Fatty liver (microvesicular steatosis)
Hepatomegaly
Elevated transaminases
Liver failure
Cardiovascular involvement
•
•
•
•
Liver biopsy showing cirrhosis in
5-year old with CESD
Type II hyperlipoproteinemia
Low HDL has been observed
Ischemic heart disease
Strokes
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LAL Deficiency ERT Phase 3 Study
Clinical Trial
NEJM 373:1010-20, 2015
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The Mitochondrion
Circuitry Model for Redox Signaling
Antioxid Redox Sig 8:1865-79, 2006
Mitochondrial Disease Therapy
•
•
•
•
•
•
•
•
•
Dichloroacetate
CoQ10
Idebenone
Nicotinamide
Riboflavin
Thiamine
Vitamin C
α-Tocopherol
α-Lipoate
•
•
•
•
•
•
•
•
Dihydrolipoate
Carnitine
Creatine
L-Arginine
Gene Therapy
Stem Cell Therapy
Transplantation
Exercise
Kerr Mol Genet Metab 99:246-55, 2010
Not all antioxidants are the same
Courtesy G. Miller
EPI-743
EPI-743 has unique redox and pharmacologic properties
Clinical candidate EPI-743
Leigh syndrome
unpublished data
Leigh Syndrome
• Caused by inherited
mitochondrial disease
– Many different mutations
• Severe brain disease
• Normal early development
• Loss of cognitive and
developmental skills
• Seizures
• Abnormal breathing
• Early death
• No therapy
HMPAO Uptake Change from Baseline
Patient 002-013
HMPAO Uptake Change from Baseline
Patient 002-013
unpublished data
Patient 002-013
Company
Drug
Indication
Trial Design
Primary
Outcome
Enrollment
Edison
EPI-743
Leigh syndrome
Phase 2B
RDBPC
NPMDS 1-3
30
Raptor
RP-103
Mitochondrial
disease
Open-label
NPMDS
Quality of life
32
Reata
RTA 408
Mitochondrial
myopathy
Phase 2
RDBPC
Exercise testing
52
Stealth Peptides
MTP-131
Mitochondrial
myopathy
Phase 1/2
RDBPC
Adverse events,
vitals, lab tests
36
Santhera
Idebenone
MELAS
Phase 2A
RDBPC
Cerebral lactate
21
Cardero
(-)-epicatechin
Becker muscular
dystrophy
Phase 1/2A
Open-label
Muscle function
and strength
10
Wellstat
PN401
Mitochondrial
disease
In development
Mitobridge
In development
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-
-
-
-
-
Summary
• Multiple therapeutic approaches possible for inborn errors of
metabolism
• Normal neurological outcome is possible
• Basic principles
– Reduce intake (tailor to specific disease)
– Decrease amount of abnormal metabolites
– Caloric support
• Solid organ transplantation
– Gene therapy with a scalpel
53