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Microglia suppression may slow photoreceptor degeneration in retinitis pigmentosa
Minocycline may inhibit the activity of these inflammatory cells, which consume photoreceptors.
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Suppressing microglial cells that prey on photoreceptors may delay the rate of photoreceptor degeneration, as occurs in retinitis pigmentosa, according to an NIH investigator.
“Although retinitis pigmentosa remains a major cause of blindness in young people, both in this country and worldwide, there is still no comprehensive treatment currently available. We wanted to better understand the disease from different angles for effective treatment that may not completely cure the disease but perhaps extend the period of time that patients retain vision.” Wai T. Wong, MD, PhD, said of the research published in EMBO Molecular Medicine.
Retinitis pigmentosa is an inherited retinal disease that typically involves a mutated gene in photoreceptors; however, fixing the gene to cure the condition is not easy.
“There are a wide variety of genes that are responsible for RP,” Wong told Ocular Surgery News. “It is difficult and time-consuming to address each and every one of those genes with individual gene therapy approaches, so ancillary treatments to slow progression can help.”
Early study
Neuroinflammation in the retina has been found in the context of retinitis pigmentosa during photoreceptor degeneration. Wong’s team, involving lead scientists Lian Zhao, PhD, Matthew K. Zabel, PhD, and Xu Wang, MD, PhD, sought to identify the source and nature of this neuroinflammation and explore if and how it contributes to photoreceptor degeneration.
Using a mouse model of retinitis pigmentosa, the investigators found that at an early phase of degeneration, resident immune cells in the retina — microglia — migrate to photoreceptors and engage in phagocytosis, whereby living but stressed photoreceptors are engulfed and digested by the microglia. In experiments in the mouse model in which microglia are depleted from the retina or their engulfing behavior is inhibited pharmacologically, photoreceptor degeneration was slowed and electrical response to light was augmented.
“In the control groups, the degeneration went forward with time as we would expect,” Wong said. “But in the intervention group, degeneration was significantly slowed down. This indicates that in addition to the nature of the mutation in photoreceptors, microglia can contribute to increasing the overall rate of degeneration. We noted that microglia were aiding and abetting the degeneration process by actively culling these endangered photoreceptors.”
Based on the observations that microglia play an active role in degeneration, along with results indicating that inhibiting the engulfing activity of microglia can save photoreceptors and increase visual function, the investigators are encouraged that the same can occur in humans to prolong the period that patients are able to see.
“Targeting microglia would not get to the root cause of the disease, but it would decrease the forces that drive degeneration,” Wong said.
Image: Wai T. Wong, MD, PhD, National Eye Institute/NIH
Continuing research
Wong is part of an ongoing phase 2 clinical trial headed by his NIH colleague Catherine A. Cukras, MD, PhD, that consists of five patients with retinitis pigmentosa who are being treated orally with minocycline, an FDA-approved broad-spectrum tetracycline antibiotic that is currently widely used to treat acne and rosacea. The medication also inhibits the activity of microglia. For the trial, 100 mg of minocycline is given twice a day. The two study endpoints are at 6 months and 12 months.
“We are banking on minocycline’s anti-inflammatory properties to decrease the activation and activity of microglia,” Wong said. In addition, the drug has a good safety profile and has been in use for decades.
Several other NEI studies are underway using minocycline to suppress microglia in other retinal diseases, including one for retinal vein occlusion, led by Cukras. Minocycline also demonstrated preliminary efficacy in the treatment of diabetic macular edema in a study that appeared in 2012 in Investigative Ophthalmology & Visual Science, led by Wong and Cukras.
“By inhibiting microglia, minocycline may have been helpful in reducing the amount of edema when used as monotherapy and may be envisioned as a possible ancillary treatment,” Wong said. – by Bob Kronemyer
- References:
- Cukras CA, et al. Invest Ophthalmol Vis Sci. 2012;doi:10.1167/iovs.11-9413.
- Zhao L, et al. EMBO Mol Med. 2015;doi:10.15252/emmm.201505298.
- For more information:
- Wai T. Wong, MD, PhD, can be reached at 6 Center Drive, Building 6, Room 217, Bethesda, MD 20892; email: wongw@nei.nih.gov.
Disclosure: Wong reports no relevant financial disclosures.