CRISPR goes mainstream: gene therapy to cure hereditary blindness in patients

In a first of it’s kind trial, scientists deliver CRISPR-Cas9 gene therapy directly into the eye of a patient with hereditary blindness.

Gene editing with CRISPR

Gene editing involves making specific changes to the DNA sequence. This is usually achieved by creating a break on a specific region of DNA and then modifying this DNA sequence by either taking away (deleting) or adding (inserting) sequence using the cells natural repair system. The goal of gene editing is to change the downstream message of a gene, thereby the function of the protein it encodes.

CRISPR (which stands for clustered regulatory interspaced short palindromic repeats) is a gene editing technology that was adapted from a naturally occurring defense system used by bacteria. CRISPR became the go to technique for gene editing around 2013 and this technology has been making great strides in advancing gene editing since then.

Tackling incurable genetic diseases

Genetic diseases result from defective genes (mutations) that are passed on from parents to children. Many of us are already be familiar with some of these inherited diseases such as hemochromatosis, Huntington’s disease, sickle cell anemia and cystic fibrosis.

The BRILLIANCE clinical trial we are highlighting here involves an eye disease called Leber’s congenital amaurosis 10 (LCA10), which affects specialized cells at the back of the eye (retina) that detects light and color. It is one of the leading causes of blindness in childhood and has no cure.

One of the most common DNA changes associated with LCA10 is in a gene called CEP290. In cells with this mutation, the CEP290 protein is produced at very low levels. Functional CEP290 protein is necessary for the normal development and function of cilia (hair like structures) found in the light-sensing cells in the retina.

Dosing CRISPR directly into the eye

This trial is a huge step forward in terms of using CRISPR-Cas9 for gene editing, because it will be the first time this editing technique will be introduced directly in to the body.

Previously, CRISPR-Cas9 has only been used to edit the genomes of cells that were first removed from the patient. Here, the components necessary for gene editing will be directly injected into the eye, near photoreceptor cells with defective CEP290.

The hope is that the mutation, which makes CEP290 inactive, will be edited or corrected “reactivating” the photoreceptor cells in the retina, to improve vision.

A phase I/II clinical trial

Clinical trials examine new treatment options in humans to gather data on the safety and the effectiveness of these new therapies. Phase I/II clinical trials often use a small number of patients where the therapy is tested. If these studies prove to be effective, the trial will move on to phase III to include a larger group of patients.

The BRILLIANCE trial will initially involve 18 patients with LCA10. Its purpose is to examine the safety, tolerability and the efficacy of using a CRISPR therapeutic called AGN-151587 (aka EDIT-101) generated by Editas medicine. A single dose of the gene therapy will be injected directly in to the eye of the patient and followed up for improvements in vision.

First patient treated

Last week marked the first milestone of the BRILLIANCE trial, when the first patient was treated at the Casey Eye Institute at Oregon Health and Science University with EDIT-101. Researchers predict the likelihood of EDIT-101 having positive outcomes will be pretty high, based on early results from another kind of therapy that has already been used to treat people with LCA10.

As we wait for the results from this first of it’s kind trial, it’s impossible not to look to the future and imagine the impact CRISPR editing will have on many other genetic diseases.

CRISPR treatment inserted directly into the body for first time (Nature News – doi: 10.1038/d41586-020-00655-8)

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