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A commentary highlights antisense oligonucleotides (AONs) targeting AASS, aiming to reduce the buildup of toxic lysine-pathway metabolites that drive pyridoxine-dependent epilepsy (PDE-ALDH7A1).
PDE-ALDH7A1 happens when a key lysine-breakdown enzyme (ALDH7A1, also called antiquitin) is not working properly, leading to accumulation of metabolites such as alpha-aminoadipic semialdehyde (alpha-AASA) and delta-1-piperideine-6-carboxylate (P6C). P6C can chemically bind pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, lowering PLP availability for brain enzymes including those involved in inhibitory neurotransmitter (GABA) biology.
Vitamin B6 treatment often stops seizures, but many children still face developmental challenges. Diet strategies (lysine restriction) and arginine supplementation can reduce metabolite load, but lysine is essential, so “turning it off” completely is not an option.
This commentary spotlights an upstream strategy: partially reducing the pathway’s input by downregulating AASS (the first enzyme in the saccharopine branch of lysine catabolism). It summarizes work using patient-derived stem cells differentiated into astrocytes (a major brain cell type for metabolic homeostasis) where PDE biomarkers and oxidative/mitochondrial stress signatures were seen, and where AASS downregulation using AONs improved those cellular readouts. The big idea is substrate reduction: reduce flux into the bottleneck so fewer toxic intermediates are made.
Why this matters
It frames a therapy concept that could complement B6 and diet: if you can safely reduce pathway flux upstream, you may reduce the chronic toxic exposure that might contribute to long-term neurological outcomes.
Limitations
This is a commentary on preclinical work and does not establish safety, dosing, delivery to the brain, or clinical benefit in people with PDE.
Sources
- “Potential of AON therapy targeting AASS: A promising molecular therapy for pyridoxine-dependent epilepsy.” Molecular Therapy – Nucleic Acids (2025). DOI: 10.1016/j.omtn.2025.102767 (PubMed: 41341747; Free full text: PMC12670543)
Safety note: This summary is educational and not medical advice.
