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Karnebeek, C.D.v.* ; Gailus-Durner, V. ; Engelke, U.F.H.* ; Seisenberger, C. ; Marschall, S. ; Dragano, N.R.V. ; da Silva Buttkus, P. ; Leuchtenberger, S. ; Fuchs, H. ; Hrabě de Angelis, M. ; Wevers, R.A.* ; Coughlin, C.R.* ; Lefeber, D.J.*

New treatment for PDE-ALDH7A1: First proof-of-principle of upstream enzyme inhibition in the mouse.

Brain Commun. 7:fcaf397 (2025)

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Pyridoxine-dependent epilepsy due to recessive ALDH7A1 mutations is characterized byintractable epilepsy that is often unresponsive to antiseizure medications. Irrespective ofpyridoxine (vitamin B6) supplementation and lysine reduction therapy, patients present severeresidual neurocognitive deficits. We evaluated upstream inhibition of 2-aminoadipicsemialdehyde synthase as a novel therapeutic strategy to reduce the accumulating metabolites (α-aminoadipic semialdehyde , Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid,and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) considered neurotoxic.We utilized an existing mouse knockout model of hyperlysinemia (Aass-knockout) andgenerated a PDE model, a Aldh7a1 single knockout model via CRISPR/Cas (clustered regularlyinterspaced short palindromic repeats and CRISPR-associated protein) and generated the double-knockout Aass/Aldh7a1 mice. Next-Generation metabolomics screening was performed tomeasure all known biomarkers in brain, liver, and plasma of wildtype and mutant mice.Metabolomics confirmed the known metabolite markers for Aldh7a1-knockout and Aassknockout mice in all samples. The potentially neurotoxic metabolites (Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid, and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) significantly decreased in double knock-out Aass/Aldh7a1 mice brain and livertissues compared to Aldh7a1-knockout mice. Plasma analysis revealed a significant reduction ofknown biomarkers, suggesting a reliable monitoring option in human patients.We demonstrate the first mammalian evidence that AASS inhibition is a viable strategy to rescueabnormal brain metabolism associated with pyridoxine-dependent epilepsy. This may target theintellectual disability and neurologic deficits caused by persistent lysine catabolic-relatedneurotoxicity despite adequate vitamin B6 supplementation.

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