Gene Therapy for X-Linked Retinitis Pigmentosa
What is X-linked Retinitis Pigmentosa?
X-linked retinitis pigmentosa (XLRP) is an incurable genetic disease that causes blindness in men, and affects approximately one in 15,000 people. The disease is caused by a defect in the RPGR 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 RPGR gene on one X-chromosome can compensate for a defective RPGR gene on the other X-chromosome to some extent. Men, however, only have one X-chromosome.
The RPGR gene encodes a special protein called X-linked retinitis pigmentosa GTPase regulator (RPGR) which plays a key role in the development 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 RPGR 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 XLRP 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 decade, with most XLRP patients becoming legally blind by the age of 40.
Gene therapy for XLRP
There are currently no effective treatments available for XLRP, 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 RPGR 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 RPGR 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 XLRP gene therapy.
The natural form of the RPGR gene has an unusual genetic code which makes it very difficult to work with in the laboratory. The genetic code for all life on Earth is made up of four letters - G, T, A and C. In the RPGR gene, however, half of the gene comprises only two letters - A and G. This makes the RPGR gene very unstable and prone to mutations, which is why XLRP is one of the more common hereditary retinal diseases.
However, a research team led by Professor Robert MacLaren from the University of Oxford has reprogrammed the genetic code of the RPGR gene to make it more stable, but in a way that does not affect its function. This has allowed the gene to be delivered reliably by an AAV vector into retinal cells.
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 16 March 2017, the first person in the world received the gene therapy for XLRP in an operation conducted at the John Radcliffe Hospital in Oxford and led by Professor Robert MacLaren.
This first-in-human Phase 1/2/3 clinical trial is a dose-escalation interventional study that will be recruiting over 60 XLRP patients in the UK and USA.
Information for Patients
UK-based XLRP patients who wish to be considered for enrolment in the clinical trial should ask their local physician to make a routine NHS referral to Professor Robert MacLaren. Overseas patients who are not NHS-eligible should contact their local physician to arrange baseline retinal scans and genetic testing. This information should be forwarded to Nightstar Therapeutics at the following email address: firstname.lastname@example.org.