a clinical trial of betaine for peroxisomal biogenesis disorders nancy braverman 1, ann moser 2,...
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A Clinical Trial of Betaine for Peroxisomal Biogenesis Disorders
Nancy Braverman1, Ann Moser2, William Rizzo3
1 McGill University, Montreal2 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 BetaineBetaine acts as a molecular chaperone to improve peroxisomal protein import of GFP-PTS1 reporter.
Control 100 mM betaine
Betaine
• 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
• 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• Plasma VLCFA, pristanic acid• RBC plasmalogens• Plasma and stool bile acids• Plasma pipecholic acid
• Safety monitoring: CBC, chemistry panel (LFTs), UA, plasma methionine, betaine
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