2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-The Effects of the Pharmacological Chaperone Sepiapterin on Phenylalanine Hydroxylase Activity of Common Variants in Phenylketonuria

The Effects of the Pharmacological Chaperone Sepiapterin on Phenylalanine Hydroxylase Activity of Common Variants in Phenylketonuria

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Researchers conducted a study to evaluate the effects of the pharmacological chaperone sepiapterin on the activity of phenylalanine hydroxylase (PAH) in different variants associated with phenylketonuria (PKU). The study utilized COS-7 cells transfected with various PAH protein variants and treated with different concentrations of sepiapterin. Results showed that sepiapterin treatment increased PAH activity in multiple variants, including those that are responsive to tetrahydrobiopterin (BH4) and those that are not. This suggests that sepiapterin acts as a pharmacological chaperone for different PAH variants beyond the known BH4-responsive ones.<br /><br />The study included two experiments: single transfection of 62 variants and cotransfection of 15 variant couplets. Enzymatic activity was determined by measuring the production of L-tyrosine using high-performance liquid chromatography. The results showed that several PAH variants had at least a two-fold increase in activity after sepiapterin treatment. Additionally, the study demonstrated that sepiapterin is converted to BH4, which acts as a cofactor for PAH, increasing its stability and providing favorable pharmacokinetics.<br /><br />The findings suggest that sepiapterin has the potential to expand the population of PKU patients who can benefit from pharmacological chaperone treatment. However, further testing of sepiapterin in a more diverse set of PAH variants is needed, as well as an analysis of the clinical correlation between PAH genotype and phenotype in PKU patients.<br /><br />Overall, this study provides evidence of the positive effects of sepiapterin on PAH activity in various PKU-associated variants. The findings support the development of sepiapterin as a potential treatment for patients with PKU. The study was funded by PTC Therapeutics, Inc.

Asset Subtitle

Submitter Only - Sarah Milner, PhD; Co-Author - Søren W. Gersting, MD; Co-Author - Madalena Barroso, PhD; Co-Author - Stefanie Etzold, Technician; Presenting Author - Neil Smith, PharmD;

Meta Tag

Genetic Testing

Genotype-Phenotype Correlations

Metabolic Disorder

Pharmacogenomics

Co-Author Søren W. Gersting, MD

Co-Author Madalena Barroso, PhD

Co-Author Stefanie Etzold, Technician

Presenting Author Neil Smith, PharmD

Submitter Only Sarah Milner, PhD

Keywords

pharmacological chaperone

sepiapterin

phenylalanine hydroxylase

PAH activity

phenylketonuria

COS-7 cells

tetrahydrobiopterin

BH4-responsive

enzymatic activity

L-tyrosine