Gene Therapy for Age-Related Macular Degeneration
What is Age-Related Macular Degeneration?
Age-related macular degeneration (AMD) currently affects more than 600,000 people in the UK and is the leading cause of vision loss. The frequency of the disease increases significantly with age, with more than 10% of the population over 70 years old showing signs of AMD. By 2020, it is predicted almost 700,000 people in the UK will have late-stage AMD.
Dry AMD, which develops when the cells of the macula become damaged by a build-up of deposits called drusen, is the most common type of AMD, accounting for around 9 out of 10 cases. It presents as a progressive and debilitating loss of vision in the centre of the visual field (macula). As the disease progresses to the atrophic form (also called geographic atrophy), characterised by the loss of the retinal pigment epithelium leading in turn to degeneration of the adjacent photoreceptor layer, the corresponding loss of central vision prevents affected patients from being able to recognise faces, drive, read, or perform other activities of daily life.
Gene therapy for Dry AMD
A key factor in dry AMD is the complement system, a system of proteins in our immune system that fights bacteria. In dry AMD, these proteins are over-active and start to attack the retinal cells, in a similar way to how they would attack bacteria. There are currently no effective treatments available for dry AMD, 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 copies of a gene producing a proprietary protein developed by Gyroscope Therapeutics called GT005, which counteracts the inflammation caused by the complement system, 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 dry AMD 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 17 January 2019, Janet Osborne became the first person in the world to receive gene therapy for dry AMD 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 gene therapy for dry AMD administered by subretinal injection and also using the proprietary OrbitTM subretinal delivery system (SDS), which was designed and optimised for precise microinjection into the subretinal space. The Orbit SDS uses a flexible cannula designed to contour the globe and access the back of the eye, targeting a subretinal location in the posterior segment. The procedure enables precise delivery of a specific dosage of infusate to the subretinal space without removing the vitreous body or creating a retinotomy, thus avoiding potential vitrectomy- and retinotomy-related complications. As the possibility of efflux of vector suspension into the vitreous body is eliminated, the likelihood of inflammation is also greatly reduced. (See surgical video.)
Following the positive interim results of this first-in-human Phase 1/2 clinical trial, a Phase 2 clinical trial will be conducted to evaluate the safety and efficacy of the gene therapy in patients with dry AMD who have rare variants in their Complement Factor I (CFI) gene, associated with low levels of the CFI protein in their blood. A parallel Phase 2 clinical trial will evaluate the safety and efficacy of the gene therapy in a broader group of patients with dry AMD.
INFORMATION FOR PATIENTS
UK-based dry AMD patients who wish to be considered for enrolment in the Phase 1/2 clinical trial should ask their local physician to arrange baseline retinal scans and genetic testing. This information should be forwarded to Gyroscope Therapeutics at the following email address: firstname.lastname@example.org.