By Hemant Khanna
In recent months, even as our attention has been focused on the coronavirus outbreak, there have been a slew of scientific breakthroughs in treating diseases that cause blindness.
Researchers at U.S.-based Editas Medicine /zigman2/quotes/200426846/composite EDIT -0.30% and Ireland-based Allergan (now owned by AbbVie /zigman2/quotes/202428675/composite ABBV -5.52% ) have administered CRISPR for the first time to a person with a genetic disease . This landmark treatment uses the CRISPR approach to a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensing compartment of the eye, called the retina, and leads to loss of the light-sensing cells.
According to the World Health Organization, at least 2.2 billion people in the world have some form of visual impairment. In the United States, approximately 200,000 people suffer from inherited forms of retinal disease for which there is no cure. But things have started to change for good. We can now see light at the end of the tunnel.
I am an ophthalmology and visual sciences researcher, and am particularly interested in these advances because my laboratory is focusing on designing new and improved gene therapy approaches to treat inherited forms of blindness.
The eye as a testing ground for CRISPR
Gene therapy involves inserting the correct copy of a gene into cells that have a mistake in the genetic sequence of that gene, recovering the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. That is because the eye is the most exposed part of our brain and thus is easily accessible.
The second reason is that retinal tissue in the eye is shielded from the body’s defense mechanism, which would otherwise consider the injected material used in gene therapy as foreign and mount a defensive attack response. Such a response would destroy the benefits associated with the treatment.
In recent years, breakthrough gene therapy studies paved the way to the first-ever Food and Drug Administration-approved gene therapy drug, Luxturna TM , for a devastating childhood blindness disease, Leber congenital amaurosis Type 2 . (Luxturna was developed by Spark Therapeutics and licensed to Novartis /zigman2/quotes/203243705/composite NVS -3.17% /zigman2/quotes/203286410/delayed CH:NOVN -0.60% . Spark Therapeutics has since been acquired by Roche /zigman2/quotes/206324342/delayed CH:ROG -0.85% /zigman2/quotes/208994986/composite RHHBY -2.69% .)
This form of Leber congenital amaurosis is caused by mutations in a gene that codes for a protein called RPE65. The protein participates in chemical reactions that are needed to detect light. The mutations lessen or eliminate the function of RPE65, which leads to our inability to detect light — blindness.
The treatment method developed simultaneously by groups at University of Pennsylvania and at University College London and Moorefields Eye Hospital involved inserting a healthy copy of the mutated gene directly into the space between the retina and the retinal pigmented epithelium, the tissue located behind the retina where the chemical reactions takes place. This gene helped the retinal pigmented epithelium cell produce the missing protein that is dysfunctional in patients.
Although the treated eyes showed vision improvement, as measured by the patient’s ability to navigate an obstacle course at differing light levels, it is not a permanent fix . This is due to the lack of technologies that can fix the mutated genetic code in the DNA of the cells of the patient.
A new technology to erase the mutation
Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering into the next phase. This breakthrough gene - editing technology, which is called CRISPR, enables researchers to directly edit the genetic code of cells in the eye and correct the mutation causing the disease.
Children suffering from the disease Leber congenital amaurosis Type 10 endure progressive vision loss beginning as early as one year old. This specific form of Leber congenital amaurosis is caused by a change to the DNA that affects the ability of the gene — called CEP290 — to make the complete protein. The loss of the CEP290 protein affects the survival and function of our light-sensing cells, called photoreceptors.
One treatment strategy is to deliver the full form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too big to be cargo for viruses. So another approach was needed. One strategy was to fix the mutation by using CRISPR.