pigmentosa (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
People with RP start to experience vision
loss in childhood, and many are blind by the time they reach adulthood.
Currently, there is no cure or effective treatment for RP, which affects
about one in 4,000 people worldwide.
‘Vision loss associated with a form of retinitis pigmentosa can be slowed dramatically by reprogramming the metabolism of photoreceptors, or light sensors, in the retina.’
Columbia University Medical Center (CUMC) researchers have
demonstrated that vision loss associated with a form of retinitis
pigmentosa can be slowed dramatically by reprogramming the
metabolism of photoreceptors, or light sensors, in the retina.
study, conducted in mice, represents a novel approach to the treatment
of RP, in which the therapy aims to correct downstream metabolic
aberrations of the disease rather than the underlying genetic defect.
The findings were published online today in the Journal of Clinical Investigation
"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," said study
leader Stephen H. Tsang, the László Z. Bitó Associate Professor
of Ophthalmology, Pathology and Cell Biology, and the Institute of
Human Nutrition. "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."
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. In an earlier paper, Dr. Tsang and his
colleagues 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," said Dr. Tsang.
Dr. Tsang 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. Overall, the metabolomes (all of the metabolites
found in an organism) of the treated mice had accumulated the molecules
needed to build the outer segment. In addition, both rods and cones
survived longer in the treated mice than in the 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," said Dr. Tsang.
"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," according to Vinit B. Mahajan, a
contributing researcher from the University of Iowa. The inhibitors
include enzyme blockers called thiomyristoyl peptides, a common plant
pigment known as quercetin, and vitexin, a substance derived from the
English Hawthorn tree.
Dr. Tsang noted, "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."