Scientists have engineered a genetic weapon that, in animal models, can forestall a common form of progressive blindness. The therapy uses a designer ribozyme, a short strand of RNA that chops up other RNA, to seek and destroy mutant RNA before it can be used to build a protein that kills the eye's rod cells. The finding could pave the way for new treatments for the blinding mutations that afflict nearly 1 in 3000 North Americans with autosomal dominant retinitis pigmentosa (ADRP).
ADRP begins to take its toll in late childhood. As the mutant rhodopsin protein kills light-sensitive rod cells in the retina, the sufferer first loses night vision, then peripheral vision, and finally central vision when the lack of rod cells causes the color-sensitive cone cells to degenerate. Like almost all autosomal dominant diseases, ADRP wreaks its havoc because one copy of a gene produces a mutant--and damaging--protein, in this case a mutant rhodopsin.
In the current Nature Medicine, Alfred Lewin, a molecular geneticist and microbiologist at the University of Florida in Gainesville, and graduate student Kimberly Drenser and their colleagues report that they developed two ribozymes, one shaped like a hairpin and the other like a hammerhead, that home in on the mutant messenger rhodopsin RNA and slice through it before it can be used as a template to assemble the harmful protein. The ribozyme is delivered via a harmless recombinant virus and turned on by a promoter active only in rod cells. They tested it in a rat model of ADRP and found that after 2 to 3 months, eyes that had been injected with the virus-ribozyme combo contained 30 to 40% more rod cells than eyes that received a dummy injection.
"This is a dramatic demonstration that ribozymes may be selective enough to recognize a mutant form of a gene while potentially not interfering at all with the [nonmutant] form," says microbiologist and molecular geneticist Tom Burke of the University of Vermont in Burlington. Scientists hope that ribozymes might be effective weapons against other autosomal dominant diseases such as Huntington's disease and glaucoma. If continuing animal studies show that the method is safe and effective, the researchers hope to proceed with Phase 1 clinical trials within a few years.