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Genome editing eye treatment a step closer

27/06/2018By Matthew Woodley
Researchers have restored retinal function in mice with retinitis pigmentosa (RP) by successfully applying CRISPR technology to a dominant disorder for the first time.

The breakthrough was made possible following the development of a more agile CRISPR tool by scientists at Columbia University, led by clinical geneticist Dr Stephen Tsang. Tsang described the procedure as “genome surgery” as the technique allowed him to remove a specific gene and replace it with a functioning one, regardless of the subject’s individual genetic profile.

“Genome surgery is coming, [and] ophthalmology will be the first to see genome surgery before the rest of medicine.”
Stephen Tsang, Columbia University.

“Genome surgery is coming, [and] ophthalmology will be the first to see genome surgery before the rest of medicine,” Tsang said.

CRISPR gene editing technology was first introduced in 2012, but diseases like autosomal dominant RP have presented a special challenge to researchers, as the affected person inherits only one copy of a mutated gene from their parents and one normal gene on a pair of autosomal chromosomes.

As a result, CRISPR-wielding scientists have needed to discover a method to edit only the mutant copy without altering the healthy one.

To achieve this, Tsang said he used a so-called “ablate-and-replace” strategy, which allowed him to develop CRISPR toolsets for all types of mutations that reside in the same gene. This is especially helpful when several types of mutations can lead to the same disorder, such as RP, which can result from any one of more than 150 mutations in the rhodopsin gene.

Typically, CRISPR researchers design a short sequence of code called guide RNA that matches the part they want to replace. They attach the guide RNA to a protein called Cas9, and together they roam the cell's nucleus until they find a matching piece of DNA.

Cas9 then unzips the DNA and pushes in the guide RNA, before it snips out the bad code and coaxes the cell to accept the good code, using the cell’s natural gene repair machinery. However, Tsang refined this process by designing two guide RNAs to treat autosomal dominant RP caused by variations in the rhodopsin gene – a critical therapeutic target as mutations can cause about 30% of autosomal dominant RP and 15% of all inherited retinal dystrophies.

Tsang said his method allowed for a larger deletion of genetic code that permanently destroys the targeted gene, increasing the chance of disrupting it from 30% to 90%.

The team completed the process by combining this method with a gene replacement technique that used an adeno-associated virus to carry a healthy version of the gene into the retina.

An electroretinogram was used to evaluate the mice following the procedure, and it showed they had achieved significant improvement in retinal function. Tsang has said he hopes to begin clinical trials within three years and apply the same technology to other inherited diseases such as corneal dystrophy, Huntington’s disease, and Marfan syndrome.

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