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Gene Therapy for Leber Congenital Amaurosis

Posted by Ilena Di Toro | Posted on May 11, 2021

Leber Congenital Amaurosis (LCA) is a genetic eye disease that affects the retina. It is caused by a mutation in 14 genes that have a role in the development of the retina. Visual impairment starts in infancy and for the most part remains stable, though it can get worse over time. Those with LCA experience an increased sensitivity to light, involuntary eye movements and extreme farsightedness.

Genetic therapy is one way to improve vision in people with LCA. There are two therapies out there that have shown promise. One is the CRISPR application. CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a genome technology that can be programmed to target specific parts of genetic code and edit DNA in precise locations. The other is gene augmentation therapy.

Since LCA is caused by mutation in the genes that leads to the development of the retina. CRISPR can be used to repair the mutations. The pupils of LCA sufferers don’t expand or contract normally in response to light. How CRISPR would fix this is that a sequence of guide RNA that matches the target DNA sequence is introduced into the cell’s nucleus and the cell makes the necessary repairs.

What makes CRISPR unique among genetic therapies is that instead of merely inserting a healthy copy of the defective gene, CRISPR aims to fix the gene in question. Treatments utilizing CRISPR started in fall 2019 and will last three years.

The other therapy is gene augmentation. It started with a Briard dog by the name of Lancelot who has LCA. The dog was treated via gene augmentation therapy with a functional copy of the RPE65 gene by a team at the University of Pennsylvania. This treatment helped the dog to see and in 2017 this therapy received approval from the Food and Drug Administration (FDA).

While this treatment improved the vision of those with LCA, it is unknown how long the effects will last. Researchers recently went back to the dogs to learn more about the outcome of their work. Researchers found that the magic number was 63. They found that when the treatment was given to dogs that had more than 63 percent of their normal photoreceptor cells, the effects of the therapy was long lasting. Conversely, when the dogs had fewer than 63 percent of their photoreceptor, the disease continued on, despite a brief restoration of sight. So, there is a concern that the improvement in vision won’t last, as a result of the disease progression. One avenue to pursue is to utilize other therapies while doing gene therapy. Doing that could lead to improved outcomes.

While CRISPR and gene augmentation therapy still have hurdles to overcome, they do show promise as treatments to restore functional vision.


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