The findings were published in the journal EMBO Molecular Medicine.
Retinitis pigmentosa, an inherited disorder that affects roughly 1 in 4,000 people, damages the retina, the light-sensitive tissue at the back of the eye. Research has shown links between retinitis pigmentosa and several mutations in genes for photoreceptors, the cells in the retina that convert light into electrical signals that are sent to the brain via the optic nerve. In the early stages of the disease, rod photoreceptors, which enable us to see in low light, are lost, causing night blindness. As the disease progresses, cone photoreceptors, which are needed for sharp vision and seeing colors, can also die off, eventually leading to complete blindness.
A microglial cell (green) extends spider-like arms to capture and consume rod photoreceptor cells (blue). Credit: Dr. Wai Wong, NEI. |
Phagocytosis is a normal process in healthy tissues and is a key way of clearing away dead cells and cellular debris. However, 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.
The researchers feel that the findings suggest therapeutic strategies that inhibit microglial activation may help decelerate the rate of rod photoreceptor degeneration and preserve vision.
What triggers microglia to go on this destructive feeding frenzy? 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 is like ringing a dinner bell that 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.
A clinical trial (NCT02140164) is already underway 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.
Source: NEI
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