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Cited by 48Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchPharmacogenetics and Drug Metabolism

START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients

Utz, Jeanine R. Jarnes, Lorentz, Cindy Pham, Markowitz, Dorothy, Rudser, Kyle D., Diethelm-Okita, Brenda, Erickson, David, Whitley, Chester B.·2012·Molecular Genetics and Metabolism
DOI 10.1016/j.ymgme.2011.10.014
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Abstract

Unlabelled Sapropterin dihydrochloride, a synthetic tetrahydrobiopterin (BH4), works as a chaperone of phenylalanine hydroxylase (PAH) in phenylketonuria (PKU) to facilitate and stabilize folding of PAH into its most active conformation. No standard pharmacogenetic tests exist to identify responsive genotypes. Previous studies have failed to identify genotypes that consistently predict response; they are weakened by varied: 1) doses; 2) response definitions; 3) duration; 4) phenylalanine (PHE) test times during different protein catabolic states; 5) control of dietary PHE. START (sapropterin therapy actual response test) protocol is a double blind, placebo-controlled, 4-week clinical test that obviates the confounders aforementioned. START results were evaluated for response-genotype correlates and trends in molecular characteristics.Results Seventy-four patients completed START. Thirty-six patients (48.6%) responded, 55 patients' genotypes are known, 38 unique genotypes are present. Alleles consistently associated with response include Y414C (8/8 patients, 6 genotypes) and I65T (9/9 patients, 6 genotypes). The p.R408W mutation, in which substitution of straight chain arginine with bulky aromatic amine, tryptophan, at the crux of a strategic hinge site activating folding of PAH, amino acid sequence 408, was strongly associated with non-response (21/29 patients non-responsive, 12/17 genotypes non-responsive). Genotypes containing at least one allele with ≥25% residual activity compared to wild type, were strongly associated with response.Conclusions The START protocol provides a rigorous pharmacogenetic test to identify sapropterin responsiveness and genotypes associated with responsiveness and non-responsiveness. Some genotypes were found to be predictive of responsiveness or non-responsiveness, and responsiveness was associated with specific alleles. The START protocol provides a reliable test for sapropterin responsiveness and will continue to improve understanding of how PKU mutations impact PAH protein-folding dynamics and enhance understanding of PKU disease and its management.

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  • Sapropterin is the first non-dietary FDA-approved synthetic BH4 for phenylketonuria and lowers blood phenylalanine by stabilizing and increasing PAH activity.

    “Sapropterin (Kuvan) is the first non-dietary, FDA-approved, synthetic form of BH4 for patients with phenylketonuria that is effective in lowering blood Phen levels by stabilizing and increasing PAH activity”

    From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Utz et al., 2012

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Authors
Utz, J. R. J., Lorentz, C. P., Markowitz, D., Rudser, K. D., Diethelm-Okita, B., Erickson, D., & Whitley, C. B.
Affiliations
University of Minnesota (US)
Corresponding author
Utz, Jeanine R. Jarnes
ORCID
Venue
Molecular Genetics and Metabolism
Publisher
Elsevier BV
Published
2012-02
Volume
105
Issue
2
Pages
193-197
ISSN
1096-7192 (ISSN-L)
DOI
10.1016/j.ymgme.2011.10.014
OpenAlex
W2127684592
Cited by
48
References
25
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 3
FWCI
3.25
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Genetics and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
University of Minnesota
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
phenylketonuria, sapropterin dihydrochloride, tetrahydrobiopterin, phenylalanine hydroxylase, pharmacogenetics, protein folding
MeSH terms
Adult, Alleles, Biopterins, Child, Preschool, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme Activation, Female, Genotype, Humans, Male, Mutation, Phenylalanine, Phenylalanine Hydroxylase, Phenylketonurias

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