Targeting the ABCA1 cholesterol transporter to correct pathophysiological myelin formation in hereditary neuropathies - Summary/abstract Myelin, a specialized, lipid-rich membrane, insulates axons and facilitates the conduction of nerve impulses from the neuronal cell body to the synaptic terminal. Disorders of myelin such as multiple sclerosis and demyelinating peripheral neuropathies cause complex neurological symptoms, with progressive pain and disability. Neither a cure nor disease-modifying treatment for patients with demyelinating neuropathies is available, which is the focus of our efforts. Cholesterol is essential and rate-limiting for myelin biogenesis by oligodendrocytes in the central nervous system and by Schwann cells in the periphery. Recently, we discovered that peripheral myelin protein 22 (PMP22), an integral membrane protein of Schwann cell myelin, is critical for cholesterol metabolism, through a functional partnership with the ATP-binding cassette subfamily A transporter (ABCA1) to provide cholesterol- access for myelin production. Notably, over 70% of heritable peripheral demyelinating neuropathies are due to abnormalities in the PMP22 gene, including increased gene-dosage (gene duplication), haploinsufficiency (gene deletion or truncation mutations), and point mutations. In each of these conditions, cholesterol is mislocalized within Schwann cells, indicating a shared subcellular pathology among these disorders. Artery Therapeutics, a collaborator for this project, developed a platform technology for therapeutic ABCA1 agonists and following a lead optimization, have identified a lead drug (CS6253). This drug cleared IND status on May 20, 2022, and is now in Phase 1 human testing for the indication of APOE4-associated dementia, including Alzheimer’s disease. Therefore, the current application is for re-purposing this novel candidate drug for ABCA1-directed therapeutics in demyelinating neuropathies. Our unpublished data with the peptide indicates efficacy in restoring functional cholesterol access via correcting cholesterol distribution, and thereby supporting myelin formation by neuropathic Schwann cells. Preliminary in vivo studies show efficacy in improving nerve conduction velocity in validated animal models. The current project will advance these findings by rigorous in vivo testing of the experimental reagent in distinct neuropathic mouse models. If successful, this lead candidate drug can quickly move to clinical trials for testing in neuropathic patients.
