A Clinical Trial of Betaine for
Peroxisomal Biogenesis Disorders
Nancy Braverman1, Ann Moser2, William Rizzo3
1
McGill University, Montreal
2 Kennedy Krieger Institute, Baltimore
3 University of Nebraska Medical Center, Omaha
Peroxisomal Biogenesis Disorders
• Clinical features
– Neonatal hypotonia, feeding problems
– Developmental delay
– Dysmorphic facial features
– Seizures
– Sensorineural deafness
– Hepatic dysfunction, adrenal insufficiency
• Zellweger syndrome, neonatal ALD, infantile
Refsum disease
Biochemical Abnormalities
• PEX gene defects – impaired peroxisomal
protein import & peroxisome assembly
• Biochemical abnormalities
– Peroxisomal β-oxidation - VLCFA, pristanic acid
– Plasmalogen synthesis - RBC plasmalogens
– Bile acid synthesis - bile acid precursors (DHCA,
THCA)
– Lysine degradation - pipecholic acid
Rationale for Betaine
Betaine acts as a molecular chaperone to improve
peroxisomal protein import of GFP-PTS1 reporter.
Control
100 mM betaine
Concentration Dependence of Betaine
Concentration and Time Dependence of
Betaine in G843D/fs1700 Fibroblasts
Betaine has Additive Effect with
Flavonoids for GFP-PTS1 import
Betaine 25 mM
Flavonoids 5μM
Betaine
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FDA approved for homocystinuria
Good safety profile - rare GI problems
Usual dose: up to 6 g per day (divided TID)
Used in clinical studies of Rett and Angelman
syndrome at up to 12 g per day w/o side
effects
Clinical Trial of Betaine for PBD
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Study sites: Omaha and Montreal
Open study design, non-blinded
12 subjects
Enrollment criteria:
– PEX1 genotype: G843D/null mutation or
homozygous G843D/G843D
– Expected survival >6 mo
• Endpoints: biochemical response after 6 mo
Clinical Trial of Betaine for PBD
• Betaine daily dose (÷ 3 times per day)
– Age < 3 years: 3 g
– Age > 3 years: 6 g
– Dose escalation over 4-6 weeks
• Increase dose at 3 months
– Age < 3 years: 6 g
– Age > 3 years: 12 g
Clinical Trial of Betaine for PBD
• Peroxisome biochemical tests at:
– Baseline, 3 mo and 6 mo
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Plasma VLCFA, pristanic acid
RBC plasmalogens
Plasma and stool bile acids
Plasma pipecholic acid
• Safety monitoring: CBC, chemistry panel
(LFTs), UA, plasma methionine, betaine
Clinical Trial of Betaine for PBD
• Betaine supplied by Rare Disease Therapeutics
and Orphan Europe
• Funded by Global Foundation for Peroxisomal
Disorders