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. 2025 Sep:218:104940.
doi: 10.1016/j.neures.2025.104940. Epub 2025 Jul 11.

Asfotase alfa restores PLP-dependent GABA, cystathionine, and amino acid metabolism in a mouse model of hypophosphatasia

Kathryn N Phoenix  1 , Andre Marozsan  2 , Susan Liu-Chen  2 , Lizhong Zhang  3 , Amit Mogha  3 , Yan Wong  3 , Catherine A Brownstein  4 , Raja Padidela  5
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Free article

Asfotase alfa restores PLP-dependent GABA, cystathionine, and amino acid metabolism in a mouse model of hypophosphatasia

Kathryn N Phoenix et al. Neurosci Res. 2025 Sep.
Free article

Abstract

This study assessed whether asfotase alfa treatment in Akp2-/- mice (a model of hypophosphatasia) reversibly normalizes GABA and cystathionine in brain tissue to concentrations in wild-type mice. To do this, metabolite concentrations were analyzed at postnatal days 10 and 48. The data showed that asfotase alfa treatment significantly increased GABA concentrations and significantly decreased cystathionine concentrations in Akp2-/- mice compared with vehicle-treated Akp2-/- mice (GABA: 1.28 ± 0.03 vs 0.48 ± 0.02 μmol/g [P < 0.0001]; cystathionine: 0.06 ± 0.00 vs 0.60 ± 0.02 μmol/g [P < 0.0001]). Concentrations post-treatment were similar to those in wild-type mice. Asfotase alfa withdrawal negated these effects. These analyses demonstrated that asfotase alfa restores GABA and cystathionine concentrations in a murine model of hypophosphatasia.

Keywords: Alkaline phosphatase; Enzyme replacement therapy; Gamma-aminobutyric acid; Hypophosphatasia; Mice; Vitamin B(6).

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Conflict of interest statement

Declaration of Competing Interest Kathryn N. Phoenix is a former employee of Alexion, AstraZeneca Rare Disease and a current employee of Boehringer Ingelheim Pharmaceuticals. Andre Marozsan is a former employee of Alexion, AstraZeneca Rare Disease and a current employee of Pfizer Inc. Lizhong Zhang, Amit Mogha, and Yan Wong are employees of Alexion, AstraZeneca Rare Disease and may have stock options or stock in that company. Sunsan Liu-Chen is a former employee of Alexion, AstraZeneca Rare Disease and a current employee of 3 H Pharmaceuticals. Catherine Brownstein reports past sponsored research grants from Alexion. Raja Padidela reports grants, consulting fees, speaker honoraria, and support for attending meetings from Alexion, AstraZeneca Rare Disease and Kyowa Kirin.

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