Gene Therapy for Choroideremia
What is choroideremia?
Choroideremia is an incurable genetic disease that causes blindness in men, and affects approximately one in 50,000 people. The disease is caused by a defect in the CHM gene which is located on the X-chromosome, and this is why the disease affects men and women differently. Women have two X-chromosomes and so a normal CHM gene on one X-chromosome can compensate for a defective CHM gene on the other X-chromosome to some extent. Men, however, only have one X-chromosome.
The CHM gene encodes a special protein called Rab-escort protein 1 (REP1) which plays a key role in the metabolism of the cells making up the retina, which is the light-sensitive layer (like a camera film) that lines the back of the eye. The absence of REP1 in the retinal cells causes them to die over time, resulting in a progressive degeneration of the retina and consequent loss of vision. Sight loss in choroideremia begins with ‘night blindness’ (i.e. loss of night vision) in adolescence, followed by a gradual loss of peripheral vision which results in progressively worsening ‘tunnel vision’. Ultimately, central vision is lost by the fourth or fifth decade.
Gene therapy for choroideremia
There are currently no effective treatments available for choroideremia, but we have developed a new technique of gene therapy which we believe may help to slow or even stop the degeneration. The new technique involves putting normal copies of the affected gene back into the cells of the retina to help them to function normally. In order to do this, we need to use a vector (i.e. carrier) of the normal gene that can safely bring the normal genes back into the retinal cells without harming them.
The vector that we use is a small virus known as adeno-associated virus (AAV), which is non-pathogenic (i.e. not known to cause disease). AAV is notably effective at getting into retinal cells, and so a modified strain of this virus is used as the vector for our choroideremia gene therapy.
In order to administer the AAV vector, the eye's clear internal jelly must first be removed by a type of 'key-hole' surgery known as a vitrectomy. This procedure is quite safe, and the eye's clear internal jelly is gradually restored by the body in the weeks following the surgery.
After the vitrectomy, a small volume of fluid containing the AAV vector is injected underneath the retina through a very fine needle that is narrower than a human hair, creating a small fluid-filled blister or bleb under the retina. This small area of retinal detachment is temporary and disappears over about 24 hours as the fluid gets slowly absorbed by the retina. This type of surgery normally lasts about an hour, and the operation itself (without the gene therapy) is a routine procedure for patients with conditions such as retinal detachment.
On 24 November 2011, Jonathan Wyatt became the first person in the world to receive the gene therapy for choroideremia in an operation conducted at the John Radcliffe Hospital in Oxford and led by Professor Robert MacLaren.
This first-in-human Phase 1/2 clinical trial was designed to test the safety and efficacy of the choroideremia gene therapy at two doses of viral vector, with 6 patients initially treated with the low dose vector, followed by another 8 patients with the standard dose vector.
The publication in The Lancet in 2014 of the promising initial outcomes observed in the first 6 patients was followed by the publication of additional data in the New England Journal of Medicine in 2016 providing evidence of the long-term benefit of the gene therapy for choroideremia.
In 2016, a follow-up Phase 2 clinical trial commenced, treating 30 more choroideremia patients with the standard dose of viral vector used in the original Phase 1/2 clinical trial. In 2018, an international Phase 3 clinical trial was launched based on the successful results of the initial Phase 1/2 clinical trial, which were published in Nature Medicine. The Phase 3 clinical trial, which is recruited 170 participants internationally, is the largest gene therapy trial in the world to date.