Unlocking Precision Medicine in Psychiatry: Targeting KAT III as a unique Concept for the Treatment of Immune-induced Cognitive Impairment and Psychosis.

The kynurenine pathway, generating neuroactive metabolites, plays a crucial role in mental processes. Excess of kynurenic acid (KYNA), driven by immune activation, triggers psychosis and cognitive dysfunction. This project aims to reduce brain KYNA by developing kynurenine aminotransferase (KAT) III inhibitors.

Traditionally, KAT II dominates KYNA production; however, our research reveals that immune activation induces KAT III. Together with SciLifeLab DDD, we have developed potent, brain-penetrant, and patentable KAT III-selective molecules.

Our research encompasses five work packages where we will a) perform in vivo proof-of-concept studies of our developed KAT III inhibitors and assess KAT II and KAT III inhibition´s comparative efficacy in curbing KYNA production in immune-induced states. b) Investigate KAT III inhibition´s impact on dopamine neurotransmission and cognition. c) Develop antisense oligonucleotids (ASOs) for KAT III. d) Utilize brain-specific cellular models to investigate the efficacy of ASOs to prevent KYNA production, and to elucidate KAT II and KAT III localization and their specific roles in KYNA production. e) Develop biomarkers for patient selection for KAT III inhibitor treatment and to verify treatment response.

This project may revolutionize psychiatric care with tailored treatments for immune-induced cognitive impairment or psychosis. Through interdisciplinary collaboration, we aim to advance psychiatry into modern precision medicine´s forefront.