Researchers at the Massachusetts Eye and Ear/Harvard Medical School Department of Ophthalmology have taken a first step in solving the problem of preserving photoreceptor cells and avoiding irreversible vision loss in patients following retinal detachment.
Degeneration of photoreceptors is a primary cause of vision loss worldwide. Identifying the underlying causes surrounding photoreceptor cell death is paramount in order to develop new treatment strategies to prevent their loss. Retinal detachment and subsequent degeneration of the retina can lead to progressive visual decline due to photoreceptor cell death. Since photoreceptors are non-dividing cells, their loss results in irreversible visual impairment even after successful retinal reattachment surgery.
New research led by Kip M. Connor, PhD, a researcher and assistant professor of ophthalmology at Mass Eye and Ear, and colleagues analyzed innate immune system regulators in the eyes of human patients with retinal detachment and correlated their findings in an experimental model. They discovered that there was a significant increase in the immune system’s alternative complement pathway following retinal detachment and that this pathway facilitated early photoreceptor cell death after injury. Injured photoreceptors lose important proteins that normally protect them from complement-mediated cell death, allowing for selective targeting by the alternative complement pathway. Additionally, by blocking the alternative complement pathway, through both genetic and pharmacologic means, photoreceptors were protected from cell death. “When photoreceptors in a detached retina were removed from their primary source of oxygen and nutrients, we found an increase in complement factor B, a key mediator of the alternative complement pathway that leads to photoreceptor cell death,” says Dr. Connor. “For the first time these results provide evidence that the alternative complement pathway exacerbates photoreceptor cell death and that inhibition of the pathway is protective,” said Kaylee Smith, a member of the Connor Lab and contributing author on the manuscript. Their findings were published Science Translational Medicine.
Today’s state-of-the-art surgical techniques are highly effective at physically reattaching the retina, and if surgery is timely, a positive visual outcome often results. Even so, patients often complain of permanent vision loss accompanied by changes in color vision. “Studies in both humans and animal models have shown that photoreceptor cell death is induced as early as 12 hours after detachment, indicating that early intervention could potentially preserve photoreceptors and improve the visual function of patients who undergo reattachment surgery,” says Dr. Connor. “Our research provides a new role for complement in retinal detachment, and suggests that inhibition of the alternative complement pathway may be good therapeutic target to prevent the initial photoreceptor cell loss.
“What makes this research so exciting is the potential impact it can have on our patients. Working closely with our colleagues in the clinic, we identified a challenging issue, went back to our laboratories to uncover a cause, and now have knowledge that may help us to develop therapies that will help to preserve our patients’ vision.”
NEI Study: Microglia and RP
Microglia often play a beneficial role by helping to clear dead cells and cellular debris and protect the central nervous system against infection. But a new study by researchers at the National Eye Institute shows that they also accelerate damage wrought by blinding eye disorders, such as retinitis pigmentosa. “These findings are important because they suggest that microglia may provide a target for entirely new therapeutic strategies aimed at halting blinding eye diseases of the retina,” said NEI Director, Paul A. Sieving, MD. “New targets create untapped opportunities for preventing disease-related damage to the eye, and preserving vision for as long as possible.” The findings were published in EMBO Molecular Medicine.
Research has shown links between RP and several mutations in genes for photoreceptors. In the early stages of the disease, rod photoreceptors are lost, causing night blindness. As the disease progresses, cone photoreceptors can also die off, eventually leading to complete blindness.
Lead investigator, Wai T. Wong, MD, PhD, chief of the Unit on Neuron-Glia Interactions in Retinal Disease at NEI, and his team studied mice with a mutation in a gene that can also cause retinitis pigmentosa in people. The researchers observed in these mice that very early in the disease process, the microglia infiltrate the outer nuclear layer, where they don’t usually venture. The microglia then create a cup-like structure over a single photoreceptor, surrounding it to ingest it in a process called phagocytosis. Dr. Wong and his team caught this dynamic process on video. The whole feast, including digestion, takes about an hour.
In retinitis pigmentosa the researchers found that the microglia target damaged but living photoreceptors, in addition to dead ones. To confirm that microglia contribute to the degeneration process, the researchers genetically eliminated the microglia, which slowed the rate of rod photoreceptor death and the loss of visual function in the mice. Inhibiting phagocytosis with a compound had a similar effect. The microglia seem to ignore cone photoreceptors, which fits with the known early course of retinitis pigmentosa.
“These findings suggest that therapeutic strategies that inhibit microglial activation may help decelerate the rate of rod photoreceptor degeneration and preserve vision,” Dr. Wong said.
What triggers microglia to go on this destructive feeding frenzy? Dr. Wong and colleagues found evidence that photoreceptors carrying mutations undergo physiological stress. The stress then triggers them to secrete chemicals dubbed “find me” signals, which attracts microglia into the retinal layer. Once there, the microglia probe the photoreceptors repeatedly, exposing themselves to “eat me” signals, which then trigger phagocytosis. In response to all the feasting, the microglia become activated. That is, they send out their own signals to call other microglia to the scene and they release substances that promote inflammation.
Other potential treatments for retinitis pigmentosa, such as gene therapy, are progressing, but are not without challenges. Gene therapy requires replacing defective genes with functional genes, yet more than 50 distinct genes have been linked to the disease in different families, so there’s no one-size-fits-all gene therapy. A therapy targeting microglia might complement gene therapy because it’s an approach that’s independent of the specific genetic cause of retinitis pigmentosa, said Dr. Wong.
A clinical trial is already under way at NEI to see if the anti-inflammatory drug minocycline can block the activation of microglia and help slow the progression of retinitis pigmentosa. The trial is currently recruiting participants. For more information, see https://www.clinicaltrials.gov/ct2/show/NCT02140164. REVIEW
