New insights into tetrahydrobiopterin pharmacodynamics from , a mouse model for compound heterozygote tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Florian B. Lagler (1) , Søren W. Gersting (2) , Clemens Zsifkovits (1) , Alice Steinbacher (2) , Anna Eichinger (2) , Marta K. Danecka (2) , Michael Staudigl (2) , Ralph Fingerhut (3) , Hartmut Glossmann (1) , Ania C. Muntau (2)

1 Department of Medical Genetics
2 Department of Molecular Pediatrics
3 University Children's Hospital

Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, , and mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between and indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH. In conclusion, our findings show a significant impact of the genotype on the response to BH in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects

Mots clés: phenylketonuria; tetrahydrobiopterin; pharmacodynamics; mouse model; compound; heterozygote

Florian B. Lagler, Søren W. Gersting, Clemens Zsifkovits, Alice Steinbacher, Anna Eichinger, et al.. New insights into tetrahydrobiopterin pharmacodynamics from , a mouse model for compound heterozygote tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Biochemical Pharmacology, 2010, 80 (10), pp.1563. ⟨10.1016/j.bcp.2010.07.042⟩. ⟨hal-00626236⟩