Researchers Developing Innovative Gene Therapy for Cone-Rod Dystrophy

April 17, 2014

At first blush, completely shutting down both copies of a gene might not seem like the best way to treat an inherited retinal disease. That’s because genes and the proteins they express are thought to be essential to the health and well-being of all cells in the body.

But the approach was used successfully in a Foundation-funded gene-therapy study of mice with autosomal dominant cone-rod dystrophy (adCORD) caused by mutations in the gene GUCA1A, also known as GCAP1. It is one of 10 genes that can cause adCORD, a retinal degenerative disease characterized by reduced visual acuity and color perception, as well as loss of central and daytime vision. Affected individuals are often legally blind by the age of 40. 

Led by Wolfgang Baehr, Ph.D., and Li Jiang, Ph.D., at the University of Utah, the study provided a proof-of-concept for an approach they hope to use in humans. Results were published in Frontiers in Molecular Science.

The scientists shut down the normal and the mutated copy of GCAP1, because the approach was simpler than trying to target only the defective copy, and the investigators determined that vision wasn’t compromised when the healthy copy was also shut down.

GCAP1 is a gene that leads to the production of a protein involved in phototransduction, the biochemical process in photoreceptors that converts light to electrical signals, which are sent back to the brain and interpreted as vision. However, if one of the two GCAP1 copies is defective, a toxic protein is produced and adCORD develops.

To be effective in most cases, a gene therapy for an autosomal dominant retinal disease must either shut down the defective gene copy and leave the normal copy intact, or deliver a copy of the normal gene after shutting done both copies. In some cases, scientists can override the defective copy by only delivering a normal copy.

However, Dr. Baehr’s team found that in the case of GCAP1, shutting down both copies successfully halted retinal degeneration in mice; even with no normal copy, the phototransduction process worked well and vision was preserved.

Dr. Baehr believes that the protein expressed by GCAP1 is not essential for normal vision or retinal health. However, the defective protein is toxic. 

To shut down the GCAP1, Dr. Baehr developed a gene therapy which produces messages known as short-hairpin RNA (shRNA). The shRNA block GCAP1’s naturally occurring RNA messaging system, rendering the gene inactive. 

“What is most impressive about this gene therapy approach is its simplicity,” says Stephen Rose, Ph.D., chief research officer of the Foundation Fighting Blindness. “The strategy of shutting down the gene altogether will not work for a vast majority of other retinal degenerations, but for GCAP1, it is the most straightforward therapeutic path, so it makes sense to take it.”