# Visualizing the distribution of large molecule therapeutics in optic nerve

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $201,251

## Abstract

PROJECT SUMMARY/ABSTRACT
Optic neuropathies cause damage to the optic nerve and are leading causes of visual field disturbance and
vision loss in adults. Large molecule therapeutics including recombinant antibodies (`biologics') have the
potential to revolutionize treatment of these diseases if challenges in delivering them to therapeutic targets
within the optic nerve can be overcome. Biologics have had considerable success in treating diseases of the
retina, however, intravitreally injected reagents do not enter the optic nerve in significant amounts and delivery
of therapeutics to sites of inflammation in optic neuritis therefore requires the development of alternative
strategies. Extracellular fluid in brain consists of the cerebrospinal fluid (CSF) found in the ventricles and
subarachnoid space and the interstitial fluid (ISF) found in the spaces between nerve cells. Although these
compartments are mostly separate, some exchange of solutes can occur via the paravascular spaces,
suggesting a potential route for delivery of large molecules to the interstitium, including the optic nerve.
Here we will assess the extent to which CSF solutes can accumulate in the optic nerve and test the feasibility
of delivering large molecule therapeutics to the optic nerve by intrathecal injection. Experiments in aim 1 will
focus on understanding the physiology of extracellular solute transport in the optic nerve. We will inject dextran
tracers of various size into the cisterna magna or directly into the optic nerve and follow their transport within
the optic nerve. Additional experiments will determine the effect of elevated intraocular pressure on solute
transport toward the optic nerve head and determine if deletion of the glial water channel AQP4 alters
extracellular solute transport in the optic nerve. Experiments in aim 2 will investigate how the pathways studied
in aim1 affect delivery of large molecule therapeutics to the optic nerve; we will investigate the permeability of
the optic nerve to antibodies and test delivery of an experimental therapeutic, aquaporumab, to the optic nerve.
It is expected that the completion of these experiments will generate compelling evidence for novel drug
administration routes in optic neuritis.

## Key facts

- **NIH application ID:** 9838224
- **Project number:** 5R21EY029881-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alexander James Smith
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,251
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838224

## Citation

> US National Institutes of Health, RePORTER application 9838224, Visualizing the distribution of large molecule therapeutics in optic nerve (5R21EY029881-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838224. Licensed CC0.

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