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 X-Linked Retinitis Pigmentosa
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 RPGR 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 our AAV gene therapy 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 gene therapy 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.
Phase 1/2 clinical trial
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.
The gene therapy surgery was performed using an operating microscope with integrated optical coherence tomography (OCT). This state-of-the-art operating microscope has a built-in OCT scanner which uses a laser to define the retinal layers, and these are projected into the microscope field through an internal image similar to a head-up display – enabling a vitreoretinal surgeon to see a cross-sectional scan of the retina in real time during a surgical procedure. The use of intraoperative OCT enables surgeons to track changes in retinal anatomy in real time and thereby permit very delicate or highly complex surgical operations to be conducted with an unprecedented level of precision.
The current trial is sponsored by Nightstar Therapeutics and supported by the NHS, through the National Institute for Health Research (NIHR). Up to 30 patients will be enrolled into this Phase 1/2 clinical trial, which is known as the XIRIUS study, at two sites: the Oxford Eye Hospital and the Manchester Royal Eye Hospital. The XIRIUS study is ongoing, with patients being treated at the John Radcliffe Hospital in Oxford and the Manchester Eye Hospital.
Information for Patients
In clinical trials, we need to be able to measure treatment effects and so it is important to select patients in whom we can make accurate measurements of vision. This means that patients with advanced disease in whom the vision is poor may not be suitable for trials, although they may, of course, benefit at a later date from the gene therapy once it has become an approved treatment. For this reason we are particularly interested to assess anyone with XLRP who is at an early stage of the disease.
UK-based patients who wish to be seen in Oxford should ask their local physician to make a routine NHS referral to Professor Robert MacLaren. Patients from overseas who are not NHS-eligible should contact their local physician to arrange baseline retinal scans and genetic testing. This will be helpful for a later date when patients will be recruited internationally for the Phase 3 clinical trials across North America and Europe.
For further information, please contact Nightstar Therapeutics at the following email address: firstname.lastname@example.org.