Potential Gene Therapy for RP

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Scientists have developed a gene therapy for the most common form of autosomal-dominant retinitis pigmen­tosa (RP) caused by mutations in the rhodopsin (RHO) gene—and success­fully demonstrated that it can prevent retinal degeneration in a canine model, an approach that someday could be harnessed to halt the disease in humans.

The researchers designed an adeno-associated viral vector to knock down the expression of existing RHO (both normal and mutant genes) and replace them with a normal copy of human RHO.¹ Retinal imaging and electro­retinography showed that this approach kept the rod photoreceptors healthy and prevented retinal degeneration for at least 8 months of follow-up.

NOVEL STRATEGY. Topographical maps of outer nuclear layer thickness show how the combined RHO knockdown and replacement therapy protected against severe retinal degeneration in a naturally occurring canine model of autosomal-dominant RP (right panels).

A dual-purpose approach. This strategy differs in key ways from the gene augmentation approach that led to a commercially available gene therapy (Luxturna) for Leber congen­ital amaurosis (LCA). Because LCA is autosomal recessive, that viral vector was engineered solely to transduce the retinal pigment epithelium with a single copy of the RPE65 gene to produce the missing protein.

In autosomal-dominant RP, rod photoreceptor cells express rhodopsin proteins from both normal and mutant RHO. “The mutant protein produced in the rods either interferes negatively with the wild-type protein that comes from the normal allele, or it has on its own a toxic gain of function, meaning that this protein may be toxic to the cell and kill it over time,” said William A. Beltran, DVM, PhD, at the University of Pennsylvania in Philadelphia.

The scientists concluded that their treatment would have to not only prevent the mutant gene already there from producing abnormal, toxic rhodopsin but also provide sufficient nor­mal rhodopsin protein for the rods to survive and function normally. But in order to do this, the therapy also would need to work against the more than 150 gene mutations known to cause autosomal-dominant RP. “The challenge was to develop a treatment that can address any mutation,” Dr. Beltran said.

Their solution was a dual-purpose viral vector: One part was targeted at “knocking down” all endogenous rhodopsin mRNAs, both mutant and normal, through a technique known as RNA interference. The second part consisted of normal human RHO that was modified to avoid degradation by the knockdown component.

“The rods would not be able to function, or survive over the long term, if you didn’t bring back a normal wild-type copy of RHO. The vector also delivers a gene that has been modified at some very specific sites so that it still produces the same amino acid sequence as the rhodopsin protein, but it is not knocked down at the RNA level,” said coauthor Alfred S. Lewin, PhD, at the University of Florida in Gainesville.

What’s next. The researchers will study whether the viral vector can successfully treat areas where the retina is already degenerating. “We’re going to be looking at whether we can intervene at stages that are clinically relevant—and target areas where there are still rod photoreceptor cells left that can be rescued,” Dr. Beltran said. “If we’re able to show that, that will expand the poten­tial candidates for gene therapy.”

—Linda Roach

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1 Cideciyan AV et al. Proc Natl Acad Sci U S A. 2018;115(36):E8547-E8556.

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Relevant financial disclosures—Dr. Beltran: Foundation Fighting Blindness: S; NIH/NEI: S; Research to Prevent Blindness: S; The Shaler Richardson Professorship Endowmment: S; University of Pennsylvania: P. Dr. Lewin: NEI: S; University of Florida: P.

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