Mechanism of action and impact of thiol homeostasis on efficacy of an enzyme replacement therapy for classical homocystinuria
DOKPE
- Philipp, Thilo Magnus ORCID University of Fribourg
- Bottiglieri, Teodoro Baylor Scott & White Research Institute, Dallas, TX, USA
- Clapper, Wilmelenne Travere Therapeutics, San Diego, CA, USA
- Liu, Kai Travere Therapeutics, San Diego, CA, USA
- Rodems, Steve Travere Therapeutics, San Diego, CA, USA
- Szabo, Csaba ORCID University of Fribourg
- Majtan, Tomas ORCID University of Fribourg
- 2024
Published in:
- Redox Biology. - USA: Elsevier BV. - 2024, vol. 77, no. art. 103383, p. 1-11
Cystathionine beta-synthase
Homocysteine
N-acetylcysteine
Enzyme replacement therapy
Homocystinuria
Disulfide isomerization
Plasma redox status
English
Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is characterized by elevated plasma and tissue homocysteine levels. There is no cure, but HCU is typically managed by methionine/protein restriction and vitamin B6 supplementation. Enzyme replacement therapy (ERT) based on human CBS has been developed and has shown significant efficacy correcting HCU phenotype in several mouse models by bringing plasma total homocysteine below the clinically relevant 100 μM threshold. As the reactive nature of homocysteine promotes disulfide formation and protein binding, and ERT is unable to normalize plasma total homocysteine levels, the mechanism of action of ERT in HCU remains to be further characterized. Here we showed that only a reduced homocysteine serves as a substrate for CBS and its availability restricts the homocysteine-degrading capacity of CBS. We also demonstrated that cells export homocysteine in its reduced form, which is efficiently metabolized by CBS in the culture medium. Availability of serine, a CBS co-substrate, was not a limiting factor in our cell-based model. Biological reductants, such as N-acetylcysteine, MESNA or cysteamine, increased the availability of the reduced homocysteine and thus promoted its subsequent CBS-based elimination. In a transgenic I278T mouse model of HCU, administration of biological reductants significantly increased the proportion of protein-unbound homocysteine in plasma, which improved the efficacy of the co-administered CBS-based ERT, as evidenced by significantly lower plasma total homocysteine levels. These results clarify the mechanism of action of CBS-based ERT and unveil novel pharmacological approaches to further increase its efficacy.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
-
- English
- Classification
- Pharmacology, therapeutics, toxicology
- License
- CC BY
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.redox.2024.103383
- ISSN 2213-2317
- Persistent URL
- https://folia.unifr.ch/unifr/documents/329603
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