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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $391,637

## Abstract

PROJECT SUMMARY
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system that causes
demyelination and neuron loss, mainly affecting optic nerves and spinal cord. While major advances have
been made in understanding NMO pathogenesis mechanisms, including the causal role of immunoglobulin G
autoantibodies against astrocyte water channel aquaporin-4 (called AQP4-IgG), there remain unknowns in
pathogenesis mechanisms of NMO optic neuritis, in part because of lack of suitable animal models, and unmet
needs in developing safe and effective therapies for NMO optic neuritis to prevent vision loss. This renewal
application builds on discoveries made by our lab on NMO pathogenesis mechanisms, animal models and
therapeutics. In Aim 1, rat models of NMO optic neuritis will be advanced to study pathogenesis mechanisms
and test therapeutics. Robust models of NMO optic neuritis will be developed in AQP4-IgG `seropositive' rats,
using, as needed, newly generated CD59-/- rats, NMO `superantibodies', and blood-brain barrier
permeabilization by high-frequency focused ultrasound. The hypothesis will be tested that passive transfer of
AQP4-IgG alone is sufficient to cause NMO optic neuritis. Also, building on advances in NMO T cell biology
and our newly generated AQP4-/- rats, the hypothesis will be tested that AQP4-sensitized T cells initiate and
amplify NMO optic neuritis in AQP4-IgG seropositive rats. Aim 2 will test a novel `bystander' mechanism for
tissue injury in NMO in which activated soluble complement components produced by AQP4-IgG binding to
AQP4 on astrocytes injure nearby oligodendrocytes, providing a potential explanation for the early
demyelination in NMO. Utilizing novel models and imaging methods, the hypothesis will be tested that
bystander injury is a general pathogenesis mechanism in NMO, not only for complement-dependent
oligodendrocyte injury, but also for microvascular injury. Aim 3 will advance non-immunosuppressive therapies
for NMO optic neuritis. Our lab introduced novel NMO therapies targeting AQP4-IgG and its binding to AQP4,
the classical complement pathway, granulocytes and remyelination, including an engineered high-affinity anti-
AQP4 antibody (`aquaporumab'). We propose to develop `second-generation aquaporumabs' by conjugating
an affinity-matured anti-AQP4 antibody with a complement inhibitor such as CD59, thereby targeting a
protective molecule exactly where it is needed, effectively boosting the efficacy of aquaporumab and
overcoming limitations on affinity and AQP4 binding site saturation. Also, building on recent work, we will
prioritize and test drug candidates for remyelination in NMO optic neuritis. The goal is to advance safe and
effective non-immunosuppressive drug(s) to preserve vision in NMO optic neuritis.

## Key facts

- **NIH application ID:** 10145679
- **Project number:** 5R01EY013574-19
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ALAN S VERKMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,637
- **Award type:** 5
- **Project period:** 2002-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145679

## Citation

> US National Institutes of Health, RePORTER application 10145679, Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies (5R01EY013574-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145679. Licensed CC0.

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