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. This renewal application is focused 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Duan, Tianjiao; Smith, Alex J; Verkman, Alan S (2018) Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica. J Neuroinflammation 15:294
Lee, Sujin; Cil, Onur; Diez-Cecilia, Elena et al. (2018) Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1. J Med Chem 61:3209-3217
Tradtrantip, Lukmanee; Felix, Christian M; Spirig, Rolf et al. (2018) Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. Neuropharmacology 133:345-353
Agbani, Ejaife O; Williams, Christopher M; Li, Yong et al. (2018) Aquaporin-1 regulates platelet procoagulant membrane dynamics and in vivo thrombosis. JCI Insight 3:
Phuan, Puay-Wah; Veit, Guido; Tan, Joseph-Anthony et al. (2018) ?F508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter. SLAS Discov 23:823-831
Verkman, Alan S; Yao, Xiaoming; Smith, Alex J (2018) The evolving mystery of why skeletal muscle is spared in seropositive neuromyelitis optica. J Cell Mol Med 22:2039-2040
Smith, Alex J; Verkman, Alan S (2018) The ""glymphatic"" mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation? FASEB J 32:543-551
Verkman, Alan S; Smith, Alex J; Phuan, Puay-Wah et al. (2017) The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets 21:1161-1170
Yao, Xiaoming; Verkman, Alan S (2017) Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G. Acta Neuropathol Commun 5:15
Lee, Sujin; Phuan, Puay-Wah; Felix, Christian M et al. (2017) Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye Diseases. J Med Chem 60:1210-1218

Showing the most recent 10 out of 259 publications