Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies

Investigator: Alan S. Verkman, MD, PhD
Sponsor: NIH Natl Eye Institute

Location(s): United States


Aquaporins (AQPs) are water transporting proteins expressed widely in mammalian tissues including the eye. Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, including optic nerve and retina. We focus on the AQP4 disease neuromyelitis optica (NMO), an autoimmune, inflammatory demyelinating disease primarily affecting optic nerve and spinal cord, producing optic neuritis and blindness. A defining feature of NMO is the presence of serum autoantibodies (NMO-IgG) against AQP4. The proposed research will investigate basic cellular and molecular questions in NMO (Aim 1), NMO disease pathogenesis mechanisms (Aim 2), and a new NMO therapy (Aim 3). Aim 1 will characterize the interaction of NMO-IgG with AQP4. Utilizing novel biophysical and biochemical tools effects of NMO-IgG on AQP4 function, assembly and cellular processing will be investigated, as well as downstream cytotoxicity. The hypothesis will be tested that AQP4 assembly in OAPs is crucial in NMO pathogenesis, and hence a target for therapy. Aim 2 will elucidate the mechanisms of ocular pathogenesis in NMO caused by NMO-IgG. Ex vivo (optic nerve culture) and in vivo mouse models of NMO optic neuritis will be used, as well as an engineered NMO 'super-antibody', to test the hypothesis that NMO-IgG binding to AQP4 causes complement-dependent astrocyte cytotoxicity, leukocyte recruitment and inflammation, leading to demyelination. The role of granulocytes, macrophages and NK cells will be investigated, with the goal of defining new therapeutic targets. Aim 3 will advance a new therapy of optic neuritis in NMO in which blocking of NMO-IgG binding to AQP4, the initiating pathogenic event in NMO, reduces NMO pathology. We have developed both monoclonal antibody and small-molecule approaches, which will be optimized and used in mouse models to obtain proof-of-concept that blocking NMO-IgG binding to AQP4 can reduce ocular pathology in NMO.  Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by autoantibodies against water channel aquaporin-4. The goal of this proposal is to understand how NMO autoantibodies cause optic neuritis and blindness, and to develop new therapies for NMO.