In Vitro Model Provides Evidence for C3a Antagonists as AMD Therapy

JULY 11, 2018
Emma Yasinski
Rosario Fernandez-Godino, PhD, MScRosario Fernandez-Godino, PhD, MSc
A recent study suggests that inhibiting the C3a receptor in the eye may treat macular degeneration (MD).

To the knowledge of the researchers, this is the first demonstration to show C3a can stimulate basal deposit production by normal human RPE cells.

“Further,” researchers wrote, “the data suggest that modulation of C3aR-mediated events could be a therapeutic approach for treatment of early AMD (age-related macular degeneration).”

Drusen deposits—yellow clumps of lipids and proteins which build up in the macula—are a hallmark indication of MD. As the disease progresses, more and more of these deposits accumulate.

For the past 7 years, Rosario Fernandez-Godino, PhD, MSc, an instructor in Ophthalmology at Harvard Medical School and lead author of the study, has been studying how these deposits form in the eyes of AMD patients.

Previous studies have shown that these deposits contain proteins from the complement system, which is involved in modulating immune response. C3 is one of those proteins. Other studies have also shown that genetic mutations in certain complement pathways increase the risk of macular degeneration.

The complement system has been implicated in a variety of diseases from AMD, to autoimmune disorders and cardiovascular issues. At least 100 different treatments aimed at inhibiting different parts of this system are currently in clinical trials.

Fernandez-Godino told MD Mag that while these trials haven’t provided promising results for AMD, the current study suggests that it is not yet time to give up on the idea.

“Our research supports C3 as a good target to prevent AMD progression, even though Compstatin-based drugs, which target the formation of the C3-convertase, have shown limited success in clinical trials,” Fernandez-Godino said.

There are limited options for studying the mechanisms behind MD. Donor eyes at the early stages of AMD are scarce, and it is difficult to produce reliable animal models. For this reason, Fernandez-Godino and her team have been working with human fetal retinal pigment epithelial cells to build an informative in vitro model of the disease process.

First, the team exposed their model to different concentrations of C3a for 2-4 weeks and observed the effects. After 2 weeks, TEM revealed basal deposits formed by abnormal deposits of extracellular matrix fibers. As the dose of C3a rose, so did the amount of fibers the researchers observed, though they did not quantify the exact number of fibers. The team added a C3a antagonist and found that the deposits diminished.

While the team did characterize the makeup of the deposits and elucidate some steps in the mechanisms of their formation, Fernandez-Godino emphasized that there is still much left to learn.

“Little is known about the role of C3a, beyond the fact that is an anaphylatoxin,” Fernandez-Godino said. “These results highlight new functions of C3a and may indicate unknown roles for this molecule.”

The study, "C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway," was published online in Nature Scientific Reports.

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