Leber Congenital Amaurosis is an eye disorder that primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and colour. People with the disorder typically have severe visual impairment beginning in infancy, making Leber’s the number one genetic cause of blindness in childhood. It is estimated that Leber’s affects approximately 15,000 people in the western world and many more in the rest of the world.
Now a person with Leber’s has become the first to receive a CRISPR–Cas9 gene therapy administered directly into their body. The treatment is part of a landmark clinical trial named ‘BRILLIANCE’ which is testing the ability of CRISPR–Cas9 gene-editing techniques to remove the mutations that cause the rare genetic condition. No other treatment is currently available for Leber’s.
The trial is injecting the components of the gene-editing system — encoded in the genome of a virus — directly into the eye, near to photoreceptor cells. The material is then infused back into the patient. The technique is the work of researchers at Oregon Health & Science University in Portland, who are collaborating with the pharmaceutical companies Editas Medicine of Cambridge, Massachusetts, and Allergan of Dublin.
Leber’s is a particularly attractive target for a gene-editing approach and the BRILLIANCE trial is the first to deploy the popular CRISPR–Cas9 technique — which has been hailed for its versatility and ease of design — directly in the body.
Conventional gene therapies use a virus to insert a healthy copy of the mutated gene into affected cells. But CEP290 is too large to slip the entire gene into a viral genome. Leber’s is caused by mutations in the CEP290 gene which disable light-sensing photoreceptor cells in the retina. But these photoreceptor cells are still present and alive in people with Leber’s.
With BRILLIANCE, gene editing is used to delete a mutation in the gene CEP290 that is responsible for Leber’s. The hope is that the cells can simply be ‘reactivated’ and ‘turned on’ using the CRISPR-Cas9 technique.
Early results from another therapy suggest that it might even be possible to improve vision as a result of the CRISPR-Cas9 technique. ProQR of Leiden, the Netherlands, is treating patients with Leber’s using an experimental treatment called sepofarsen. Early results suggest that sepofarsen, which uses a technique called antisense therapy to correct a Leber’s-causing mutation in RNA made from the CEP290 gene, can also improve vision.
This use of CRISPR–Cas9 in the body is a significant jump from treating cells in a dish. In ophthalmic circles, it is akin to space flight versus a regular plane trip. But if we can master this Nobel Prize-winning technology, there are reasons to be optimistic about the role that it might play in the ongoing mission to cure, alleviate and prevent blindness.