A Clinical Trial of Betaine for Peroxisomal Biogenesis Disorders Nancy Braverman 1, Ann Moser 2, William Rizzo 3 1 McGill University, Montreal 2 Kennedy.

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

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 mMFlavonoids 5μM

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

Clinical Trial of Betaine for PBD

• Betaine supplied by Rare Disease Therapeutics and Orphan Europe

• Funded by Global Foundation for Peroxisomal Disorders