THE USE OF SELECTIVE SPHINGOSINE-1-PHOSPHATE RECEPTOR 5 AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND LYSOSOMAL STORAGE DISEASES SUCH AS NIEMANN-PICK C DISEASE

Abstract

Sphingosine-1-phosphate (S1P) plays an important role as a regulator of signal transduction, cellular plasticity, cell proliferation, membrane stability (e.g. BBB integrity), and modulates the ceramide-S1P homeostasis. S1P exerts its action through G protein-coupled receptors, such as S1P5. This receptor is preferentially expressed in the central nervous system (CNS), potentially limiting peripheral side-effects. Given the modulatory role on lipid homeostasis, BBB integrity, and cellular plasticity, it is expected that S1P5 agonism might be a beneficial treatment for neurodegenerative diseases such as Alzheimer's disease (AD). AbbVie has recently developed several selective S1P5 receptor agonists, including A-971432. A-971432 is a highly selective full hS1P5 receptor agonist (EC50 = 10 nM) with excellent PK properties such as good oral bio-availability (>60% in all species), half-life (7-9h), and brain penetration (B/P ∼0.2). This compound was used to test the hypothesis that selective S1P5 agonists will a) reduce CNS, but not peripheral lipid content, b) improve cognition, and c) change disease progression as assessed in a model mimicking key features of AD. A-971432 was examined in models of age-related cognitive decline including the spontaneous alternation T-maze assay in aged (12+ months) C57BL6J mice and Morris Water Maze (MWM) and the Object Recognition (ORT) task in aged (18+ months) Wistar rats. Chronic treatment (A≥3 7 days) in either T-maze (0.03 mg/kg - 3 mg/kg) or MWM/ORT (0.1 and 0.5 mg/kg) fully reversed the age-related cognitive deficits. The minimal efficacious dose in these models (set as >90% reversal in >80% of the animals) was 0.1 mg/kg with a plasma exposure of 40 ng/mL. Concomitantly, A-971432 (A≥3 0.1 mg/kg) normalizes the age-related CNS sphingolipid imbalance without affecting plasma levels. Finally, a single dose of A-971432 was examined in the murine model of Niemann Pick C disease (NPC). NPC is a lysosomal-endosomal storage (neurodegenerative) disorder resulting in massive lipid accumulation in the CNS. NPC subjects display AD-like pathology such as A β and Tau accumulation. A-971432 (1 mg/kg) was able to improve the behavioral phenotype (dystonia, motor impairment), promote survival, normalized CNS sphingolipid content, and normalized A β levels in the CSF. The data, together with the cognition and lipid modulation data indicate that S1P5 agonism provides an innovative mechanism for the treatment of neurodegenerative disorders such as AD and lysosomal storage disorders such as Niemann Pick C.