Retinitis pigmentosa, which is the condition that causes vision loss in patients with Usher syndrome, is caused by mutations in many different genes. Research has shown that inflammation in the cells of the retina is an important contributor to progressive loss of vision in RP. This inflammation is driven by the innate immune system. This study examined several different immune mechanisms: TNFα, TLR, NLRP3, chemokines and JAK/STAT.
TNFα (Tumour necrosis factor alpha) is a signal released by immune cells and is present at high levels in the retina of those with RP. Mouse models have been used to show that reducing TNFα decreases photoreceptor death and improves function. Medications that reduce TNFα are already widely used for diseases like Crohn’s, and therefore testing these medications as therapeutics for RP is warranted.
TLRs (Toll-like receptors) help the body recognise harmful pathogens. TLR activity has been shown to increase retinal degeneration in RP models. Blocking this signaling pathway in mice increased the survival of photoreceptors. Thus, this is another target for potential therapies to treat RP.
NLRP3 is a protein known to be released as a defense against harmful stimuli. Canine models with RP exhibit increased levels of NLRP3. The antioxidant N-acetylecysteine (NAC) reduced this NLRP3 inflammatory response in mouse models of RP and improved survival of rod and cone cells.
Chemokines are another type of signal. Chemokine activity is reduced in RP retinal cell models before the photoreceptor cells begin to degenerate. Increasing chemokine release protects cone cells in mouse models of RP, suggesting that increasing these signals in patients with RP could be beneficial.
A fourth signaling pathway called JAK/STAT is involved in a wide range of functions in the body. Mouse models have indicated that this pathway may be involved in the loss of function in retinal cells seen in RP. There are many drugs that block JAK activity already being for various medical conditions. Thus, further research on these drugs as possible therapies for RP is suggested.
Early stage research has also indicated that the gut microbiome may be linked to retinal degeneration. The impact of a high-fat diet on gut microbiology may increase stress on retinal cells.
What this means for Usher syndrome: This paper highlights connections between inflammation and retinitis pigmentosa. Studies have shown that treatments that reduce inflammation could potentially protect the light-sensitive photoreceptor cells from becoming damaged. If these treatments could be proven to work in humans with retinitis pigmentosa, they would be gene agnostic. This means they would have the potential to treat retinitis pigmentosa caused by any type of genetic mutation, including Usher syndrome.
