# Anti-ceramide immunotherapy for diabetic retinopathy

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $380,566

## Abstract

Recent advances using pharmacotherapy greatly expand treatment options for diabetic
retinopathy. Intravitreal anti-VEGF immunotherapy has proven to be effective in resolving both
neovascular diabetic retinopathy (DR) and diabetic macular edema (DME). However, several large
clinical studies reveal that about 40% of patients do not respond to anti-VEGF therapy. Moreover, anti-
VEGF treatment is directed at the very late stage in the disease, when full reversal of retinal damage
is difficult. Thus, finding novel strategies to cure this complication is paramount.
 The diabetic metabolic insult leading to retinal vascular degeneration involves initial endothelial
cell damage due to low-grade chronic inflammation that is then inadequately repaired due to
compromised availability and functionality of bone marrow derived circulating angiogenic cells (CACs).
Normally migration to the site of endothelial injury and homing by CACs participates in the retinal
vascular repair process. We previously demonstrated that bone marrow pathology with CAC
dysfunction precedes and is necessary for retinal vascular degeneration in diabetes. The molecular
metabolic link connecting both initial inflammation in the retina and dysfunctional CACs involves
activation of acid sphingomyelinase (ASM), the central enzyme of sphingolipid signaling, converting
sphingomyelin into pro-inflammatory and pro-apoptotic ceramide.
 Sphingomyelin is preferentially concentrated on the outer leaflet of the plasma membrane of all
mammalian cells. Stress-induced ASM secretion leads to generation of ceramide therein. Once
generated, ceramide, due to hydrophobic forces, hydrogen bonding and van der Waal forces,
spontaneously coalesces into ceramide-rich platforms (0.5-5.0 mm diameter), macrodomains into
which proteins insert and multimerize for the purpose of transmembrane signal transmission. The
outcome of this process in retinal endothelial cells, is pro-inflammatory and apoptotic signaling. To
intervene therapeutically in microvascular inflammation and apoptosis, our program developed a set of
anti-ceramide antibodies. These antibodies are highly specific for ceramide and highly effective in
binding monomeric ceramide generated on the surface of endothelial and other cells thereby preventing
cytokine receptor clustering and pro-inflammatory and apoptotic signaling. The current application we
will employ 6B5 anti-ceramide single chain variable fragment (scFv) to prevent endothelial cell
activation and subsequent damage in the retina and to improve retinal vascular repair by correcting the
function of bone marrow derived CACs.

## Key facts

- **NIH application ID:** 10200072
- **Project number:** 5R01EY030766-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Julia V Busik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,566
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200072

## Citation

> US National Institutes of Health, RePORTER application 10200072, Anti-ceramide immunotherapy for diabetic retinopathy (5R01EY030766-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10200072. Licensed CC0.

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