Metabolic Effects of Tetrahydrobiopterin Treatment

Background: Tetrahydrobiopterin (BH4), produced in the United States as Kuvan® for the treatment of BH4-responsive phenylketonuria, has been shown in several open-label and two double-blind placebo-controlled studies conducted in Japan and Scandinavia to have efficacy in the treatment of core autism spectrum disorder (ASD) symptoms. Given the dearth of available treatments for core ASD symptoms, interest has grown for the use of Kuvan® for the treatment of ASD. A double-blind placebo-controlled study examining the efficacy of Kuvan® for the treatment of core ASD symptoms has recently been completed by the Children's Health Council (Palo Alto, CA). BH4 is known to influence neurotransmitter, nitric oxide and oxidative stress metabolism. The current study was designed to complement the Children's Health Council study by examining the metabolic effect of Kuvan® treatment using a similar treatment protocol.

Objectives: The purpose of this study was to evaluate the behavioral and metabolic effects of Kuvan® treatment on young children with language and/or social delays and to determine if metabolic biomarkers can predict behavioral response to Kuvan® treatment.

Methods: 10 participants (ages 2-6 yrs.) were entered into a 16-week open-label trial of 20mg/kg/day once-daily treatment of Kuvan®. At baseline, 8 weeks and 16 weeks, measures of language (Preschool Language Scales [PLS]) and adaptive behavior (Vineland Adaptive Behavior Scales [VABS]) as well as metabolic measures of oxidative stress (oxidized glutathione [GSSG], reduced glutathione [GSH], S-adenosylmethionine [SAM], S-adenosylhomocysteine [SAH], 3-nitroTyrosine), plasma pterins (tetrahydrobiopterin [BH4], dihydrobiopterin [BH2], biopterin [B]), and nitric oxide (arginine, citrulline, 3-nitroTyrosine) metabolism were obtained. Adverse effects were monitored throughout the trial. Repeated-measures analysis of covariance with a 0.05 alpha was used. Only significant effects are reported below.

Results: Two participants were withdrawn from the study: one from mild adverse effects and one due to non-compliance. Total and receptive PLS scores increased over the 16 weeks of Kuvan® treatment as did expressive and receptive language and personal, community, interpersonal and coping skills on the VABS. Increases in GSH, SAM and the GSH/GSSG and SAM/SAH ratios were consistent with strong improvement in transmethylation and redox pathways. Decrease in 3-nitroTyrosine was consistent with decreased peroxynitrite production. BH4 increased while BH2 and B decreased resulting in an improved reduced-to-oxidized pterin ratio (BH4/BH2+B). Citrulline changed in a non-linear manner. Higher baseline arginine-to-citrulline ratio was associated with more improvement in expressive and total PLS scores. Greater improvement in the reduced-to-oxidized pterin ratio was association with more improvement on expressive and total PLS scores and coping skills on the VABS. Greater citrulline increases were associated with greater improvement in personal, coping and play VABS skills. Kuvan® was well-tolerated.

Conclusions: Kuvan® was associated with significant improvement in the transmethylation, redox and nitric oxide pathways as well as the reduced-to-oxidized pterin ratio. Greater improvements were seen in patients with more favorable improvements in biomarkers of nitric oxide and reduced-to-oxidized pterins. These data suggest that behavioral improvement associated with Kuvan® treatment may be associated with improvements in nitric oxide metabolism.