Researchers at Duke University believe they have developed an approach to treat retinal conditions (including retinitis pigmentosa), all of which create misfolded proteins that cells in the eye cannot process. The scientists have shown that boosting the cells' ability to process misfolded proteins could keep them from aggregating inside the cell. They devised and tested the strategy in mice, significantly delaying the onset of blindness.

The team’s study (“Increased Proteasomal Activity Supports Photoreceptor Survival in Inherited Retinal Degeneration”) appears in Nature Communications.

“Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin–proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells,” write the investigators.

“We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28α, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness.”

Their technique potentially could be used to prevent cell death in other neurodegenerative diseases, such as Huntington's, Parkinson's, and Alzheimer's, said Vadim Arshavsky, Ph.D., senior author of the paper and Helena Rubenstein Foundation Professor of Ophthalmology at the Duke University School of Medicine.

“You can offer almost nothing in terms of treatment to a patient with retinitis pigmentosa or other inherited blindness today,” Dr. Arshavsky said. “This investigation provides evidence that enhancing the capacity of the cell to process misfolded proteins is worth pursuing. Another important piece is that inherited blindness is just a subset of a larger category of neurodegenerative diseases, so this concept could be tested in other conditions, as well.”

The Duke team collaborated with colleagues from the California Institute of Technology. They focused on the proteasome: machinery inside all cells that degrades misfolded proteins. Dr. Arshavsky compares the barrel-shaped structure to a paper shredder, with the cutting elements hidden inside.

Misfolded proteins must pass through a “lid” on the shredder to be processed, but cells in diseased mice do not have enough lids, enabling the buildup of the damaged proteins. Instead of trying to alter the shredders, Dr. Arshavsky and his team genetically increased the quantities of lids for the shredders, allowing cells to process more misfolded proteins.

In trials, mice with added proteasome lids retained four times the number of functional retinal cells by adulthood than mice with the same form of retinitis pigmentosa, which went blind as adults. The lids were introduced genetically in the line of lab mice. In humans, lids could potentially be added through gene therapy or drug compounds.

“If you can retain four times the number of the functional cells in the eye, that would mean decades more vision in a human patient,” Dr. Arshavsky said. “It's not a complete cure, but it's a tremendous delay. This type of treatment has the potential to defer the onset of blindness beyond the human lifespan.”

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