Progression of Retinitis Pigmentosa Slowed by Sirt6 Inhibition in Mouse Model

Retinitis pigmentosa is one of a number of forms of retinal degeneration that produce progressive blindness, though in this case it is primarily an inherited condition. Researchers here find a genetic manipulation that slows the progression of this effect. Interestingly, they are inhibiting sirt6 in a mouse model of the condition in order to obtain this outcome. In the broader context, increased levels of sirt6 have been shown to modestly extend the life of male mice. This is perhaps a helpful reminder that things are never simple when it comes to biochemistry and the manipulation of cellular metabolism. It would nonetheless be interesting to see how this approach does in forms of age-related blindness that involve retinal cell death, but since it fails to address underlying forms of molecular damage directly I'm not optimistic. Age-related retinal degeneration is strongly connected to, for example, accumulation of hardy forms of metabolic waste that form lipofuscin and disrupt cellular recycling processes. That may or may not be impacted in any way via altered sirt6 levels, but certainly targeted clearance of lipofuscin - such as the work undertaken by Ichor Therapeutics - should be a much more effective approach than tinkering with metabolism to slow down its accumulation.

Researchers have demonstrated that vision loss associated with a form of retinitis pigmentosa (RP) can be slowed dramatically by reprogramming the metabolism of photoreceptors, or light sensors, in the retina. "Although gene therapy has shown promise in RP, it is complicated by the fact that defects in 67 genes have been linked to the disorder, and each genetic defect would require a different therapy. Our study shows that precision metabolic reprogramming can improve the survival and function of affected rods and cones in at least one type of RP. Since many, if not most, forms of the disorder have the same metabolic error, precision reprogramming could conceivably be applied to a wide range of RP patients."

RP, an inherited form of vision loss, is caused by genetic defects that lead to the breakdown and loss of rods, the photoreceptors in the retina that enable peripheral and night vision. Over time, the deterioration of rods compromises the function of cones, the color-sensing photoreceptors. Rods are among the most metabolically active cells in the body. They are particularly active during periods of darkness, when they burn glucose to release energy. Researchers theorized that rods deteriorate in RP, in part, because they lose the daytime's ability to use glucose to rebuild the rods' outer segment (the light-absorbing portion of the photoreceptor). "We hypothesized that diseased rods could be rescued by reprogramming sugar metabolism."

Researchers tested this hypothesis in mice with a mutation in the Pde6 gene that disrupts rod metabolism, leading to an RP-like disorder. The mice were treated so that their rods could not express Sirt6, a gene that inhibits sugar metabolism. Examination of photoreceptors with electroretinography showed that the mice had significantly greater measures of rod and cone health than untreated controls. While the treatment significantly prolonged survival of the diseased rods and cones, it did not prevent their eventual death. "Our next challenge is to figure out how to extend the therapeutic effect of Sirt6 inhibition. Although the treatment that was used in the mice cannot be applied directly to humans, several known Sirt6 inhibitors could be evaluated for clinical use. Further studies are needed to explore the exciting possibility that precision metabolic reprogramming may be used to treat other forms of RP and retinal degeneration."



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