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A Clinical Trial of Betaine for Peroxisomal Biogenesis Disorders

A Clinical Trial of Betaine for Peroxisomal Biogenesis Disorders. Nancy Braverman 1 , Ann Moser 2, William Rizzo 3 1 McGill University, Montreal 2 Kennedy Krieger Institute, Baltimore 3 University of Nebraska Medical Center, Omaha. Peroxisomal Biogenesis Disorders. Clinical features

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A Clinical Trial of Betaine for Peroxisomal Biogenesis Disorders

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  1. 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

  2. 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

  3. 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

  4. Rationale for Betaine Betaine acts as a molecular chaperone to improve peroxisomal protein import of GFP-PTS1 reporter. Control 100 mMbetaine

  5. Concentration Dependence of Betaine

  6. Concentration and Time Dependence of Betaine in G843D/fs1700 Fibroblasts

  7. Betaine has Additive Effect with Flavonoids for GFP-PTS1 import Betaine 25 mM Flavonoids 5μM

  8. 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 Rettand Angelman syndrome at up to 12 g per day w/o side effects

  9. 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

  10. 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

  11. 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

  12. Clinical Trial of Betaine for PBD • Betaine supplied by Rare Disease Therapeutics and Orphan Europe • Funded by Global Foundation for Peroxisomal Disorders

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