Genetic Defect Causing X-Linked RP Repaired in Patient’s Cells

February 12, 2016

Stem cells derived from a patient’s blood or skin—also known as induced pluripotent stem cells (iPSCs)—have vision-saving potential for people with inherited retinal diseases such as retinitis pigmentosa (RP), Stargardt disease and age-related macular degeneration. That’s because they can be developed into photoreceptors, the cells that make vision possible, and replace those lost to retinal conditions.

A major advantage of iPSCs is there’s minimal risk they’ll be rejected by the recipient’s immune system, because the recipient is getting his or her own cells. However, a drawback to iPSC is they still have the gene mutation causing the inherited retinal condition.

Foundation-funded researchers at Columbia University, with collaborators at the University of Iowa, have made significant progress in addressing this limitation of iPSC. They used an innovative gene-editing technique known as clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9 to locate and repair the genetic defect in iPSCs from a person with X-linked RP (XLRP). This particular defect—an ORF15 mutation in the gene RPGR—is a common cause of the condition. The advancement was reported in the journal Scientific Reports.

“We still have some way to go, but we believe that the first therapeutic use of CRISPR will be to treat an eye disease. Here we have demonstrated that the initial steps are feasible,” says Stephen Tsang, M.D., Ph.D., one of the study’s lead investigators at Columbia University.

Unlike gene therapies, in which an entire healthy gene is delivered to cells to replace the mutated gene, gene editing with CRISPR/Cas9 corrects the defect in the gene through a “cut-and-paste” technique.

Gene replacement is analogous to delivering a whole new book to fix a spelling mistake in a single word in the original book. Whereas gene editing simply finds the word with the mistake in the original book and corrects it.

Gene editing may be advantageous when a replacement gene is too large to fit into the human-engineered viral delivery system used to get it into the cell. Gene editing may also be a preferred approach to treating autosomal dominant diseases, because it may be easier to just shut down the mutated gene copies while leaving normal copies intact.

A research team at Cedars-Sinai Medical Center in Los Angeles recently used CRISPR/Cas9 to prevent vision loss in rodents with a form of adRP caused by a mutation in the gene RHO.

More clinically advanced than gene editing, gene replacement therapies are in human studies for several retinal diseases, including Leber congenital amaurosis, RP, Usher syndrome type 1B, choroideremia and X-linked retinoschisis. The company Applied Genetic Technologies Corporation is working toward a clinical trial of a gene-replacement therapy for people with XLRP (RPGR mutations)