# Membrane Permeant Peptides for Imaging Cell Function

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $527,996

## Abstract

Glaucoma is an optic neuropathy characterized by selective retinal ganglion cell (RGC) degeneration
with associated excavation of the optic nerve head, and one of the leading causes of blindness in the world.
RGC death mechanisms have been shown to involve apoptosis. Examination of the optic nerve head can reveal
signs of RGC axon loss, but wide variability exists and identification of disease is challenging. Characteristic
field defects can confirm the diagnosis, but as many as 30%-50% of RGCs may be lost before defects are
detectable by standard visual field testing. Thus, better advanced diagnostics are urgently needed, especially in
high risk populations, which include older age, family history of glaucoma, black race, use of systemic or topical
steroids, and high intraocular pressure. Furthermore, slowing disease progression and preserving quality of life
are the main goals of glaucoma treatment. Indeed, several emerging therapeutic options for glaucoma, e.g.,
dietary vitamin B3 (niacin, a pre-cursor of NAD+) and overexpression of nicotinamide nucleotide
adenylyltransferase 1 (Nmnat1), would benefit from a quantitative imaging biomarker. However, there exist no
quantitative measures of RGC health to determine therapeutic effectiveness and better methods to monitor
therapy are needed.
 Previously, we designed and synthesized peptide-based imaging agents that can penetrate cells via non-
receptor-mediated endocytic pathways, gaining access to the cytosolic compartment. These cell-penetrating
optical imaging agents contain quenched fluorophores flanking target protease sequences that are cleaved and
activated by caspase-3, one key “effector” protease in cells committed to apoptosis. Upon cleavage, these
agents show caspase-3-dependent fluorescence signal amplification, thereby enabling high quality enzyme-
specific single-cell imaging of apoptosis in vivo.
 We discovered that our cell-penetrating peptides preferentially accumulate in RGCs, the predominate
cells of the retina selectively engaging endocytic pathways, and importantly, selectively injured in glaucoma.
Because these RGCs are particularly accessible through an intravitreal approach, a routine ophthalmological
procedure now performed everyday in the clinic, we are developing these cell-type-specific peptides for use in
advanced diagnostics and therapeutic monitoring (not for screening the general population). This renewal
application is focused on translation of this strategy through quantitative pre-clinical testing in advanced
glaucoma models to monitor disease progression and quantify dietary (niacin) and gene therapy (Nmnat1)
interventions, as well as toxicology analysis, and metabolite profiling. We will advance a lead peptide toward the
clinic through a unique statistically-robust non-human primate model of glaucoma. These activities benefit from
the combination expertise of this team in chemistry, molecular imaging, biochemistry, advanced animal models
and vision biology.

## Key facts

- **NIH application ID:** 10250484
- **Project number:** 5R01EY019587-21
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** David Piwnica-Worms
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,996
- **Award type:** 5
- **Project period:** 1999-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250484

## Citation

> US National Institutes of Health, RePORTER application 10250484, Membrane Permeant Peptides for Imaging Cell Function (5R01EY019587-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10250484. Licensed CC0.

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