Unmet Need
Glutamate is the primary excitatory neurotransmitter in the human brain [1]. Excessive glutamate signaling can disrupt calcium homeostasis, leading to mitochondrial dysfunction, the overproduction of reactive oxygen species, and neuron loss via necrotic or apoptotic pathways [2]. This phenomenon, known as excitotoxicity, contributes to disease pathogenesis in the settings of acute brain injury (i.e., stroke, trauma) and chronic neurodegenerative disease (i.e., ALS, Alzheimer’s disease, Huntington’s disease, schizophrenia) [3]. Therapeutic efforts to curb excitotoxicity include treatment with glutamate receptor antagonists (Memantine) [4] or with drugs that inhibit presynaptic glutamate release (Lamotrigine) [5]. These approaches have had limited clinical success, in part due to side effects from the disruption of normal neurotransmission [4,5].
Glutamate carboxypeptidase II (GCPII) is a surface membrane protein that is responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) to release glutamate and N-acetylaspartate (NAA) [6]. GCPII inhibition directly reduces glutamate levels, while also increasing levels of NAAG, a glutamate receptor agonist whose activity prevents additional glutamate release and promotes the release of TGFβ, leading to neuroprotection [6]. The utility of GCPII inhibitors has been demonstrated in animal models of neurodegenerative diseases associated with excitotoxicity, but the blood-brain barrier remains an obstacle to clinical candidate development [6]. Therefore, there is a strong need to identify GCPII inhibitors with efficient central nervous system penetration in order to address neurodegenerative disorders associated with excess glutamate signaling.
Technology Overview
Johns Hopkins researchers have identified L-DOPA, D-DOPA, and caffeic acid as novel inhibitors of GCPII. Using these compounds as scaffolds, they have synthesized prodrugs with enhanced CNS permeability. They have also explored the effectiveness of intranasal delivery for augmenting brain penetration. These novel GCPII inhibitors may provide additional therapeutic options for neurodegenerative disorders associated with excitotoxicity.
Stage of Development
Inventors have completed GCPII inhibitor design and have validated brain penetration in both mouse and primate models.
Publication
· Gori SS, Thomas AG, Pal A, Wiseman R, Ferraris DV, Gao RD, Wu Y, Alt J, Tsukamoto T, Slusher BS, Rais R. D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II. Pharmaceutics. 2022 Sep 23;14(10):2018.
· WO 2023/064783
