Exploratory study of the effect of one week of orally administered CNSA-001 (sepiapterin) on CNS levels of tetrahydrobiopterin, dihydrobiopterin and monoamine neurotransmitter metabolites in healthy volunteers

Publication date: December 2019Source: Molecular Genetics and Metabolism Reports, Volume 21Author(s): Neil Smith, Nicola Longo, Keith Levert, Keith Hyland, Nenad BlauAbstractTetrahydrobiopterin (BH4) is a cofactor for the enzymes tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes in the production of the neurotransmitters, dopamine and serotonin, respectively, in the central nervous system (CNS). Administration of BH4 is used clinically within the management of persons with genetic BH4 deficiencies, but the BH4 molecule does not cross the blood-brain barrier sufficiently. CNSA-001 is a pharmaceutical preparation of sepiapterin, a natural precursor of BH4 that induced larger increases in plasma BH4 compared with administration of the same doses of BH4 itself in healthy volunteers in a randomized trial. Here, we report the effects of 7 days of once-daily treatment with CNSA-001 60 mg/kg (n = 6) or placebo (n = 2) on metabolites of the BH4 synthetic pathway and on biomarkers of the serotonin (5-hydroxyindoleacetic acid [5-HIAA]) and dopamine (homovanillic acid [HVA]) pathways in cerebrospinal fluid (CSF) in subjects from this trial. There were no notable changes in any metabolite in placebo-treated subjects. Administration of CNSA-001 increased mean BH4 from 18.1 (SD 3.0) to 35.1 (10.0) nmol/L, and of dihydrobiopterin (BH2) from 2.1 (0.3) to 7.9 (1.5) nmol/L. Overall, administration of CNSA-001 had little effect on mean levels (pre- vs. post-t...

Source: Molecular Genetics and Metabolism Reports - August 12, 2019 Category: Genetics & Stem Cells Source Type: research