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

摘要

Tetrahydrobiopterin (BHsub4/sub) 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 BHsub4/sub is used clinically within the management of persons with genetic BHsub4/sub deficiencies, but the BHsub4/sub molecule does not cross the blood-brain barrier sufficiently. CNSA-001 is a pharmaceutical preparation of sepiapterin, a natural precursor of BHsub4/sub that induced larger increases in plasma BHsub4/sub compared with administration of the same doses of BHsub4/sub 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 BHsub4/sub 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 BHsub4/sub from 18.1 (SD 3.0) to 35.1 (10.0) nmol/L, and of dihydrobiopterin (BHsub2/sub) 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-treatment) of 5-HIAA (76.1 [SD 29.8] vs. 70.1 [23.1] nmol/L) or HVA (177.2 [66.5] vs. 184.8 [35.3]) nmol/L. One subject with low 5-HIAA and HVA at baseline responded with approximately three-fold increases in CNS levels of these metabolites after CNSA-001 treatment, with post-treatment levels within the range of those seen in other subjects. Administration of CNSA-001 60?mg/kg markedly increased levels of BHsub4/sub in the CNS of healthy volunteers, with apparently little overall effect in CNS levels of already normal key neurotransmitter metabolites.