Professor Robin Ali
Professor of human molecular genetics at the Institute of Ophthalmology, University College London.
Professor Robin Ali is an MRC-funded scientist working at the forefront of not one, but two, fields of regenerative medicine: gene and stem cell therapy.
The eye is fertile ground for developing new therapies, a feature that Professor Robin Ali is taking full advantage of. Not content with a thriving gene therapy programme, he took up the challenge of entering the world of stem cell therapy in 2004 when the MRC was funding researchers to move in from other fields.
Robin’s research focuses on therapies for retinal disorders, mainly those that affect the light-sensitive ‘photoreceptor’ cells of the eye. Many of these are rare, single-gene disorders that cause vision loss over time — and which have no treatments.
Lucky for Robin, “the properties of the eye lend it to experimental interventions,” he says. It is fairly straightforward to operate on, and the progress of a therapy — improved retinal sensitivity, for example — can be easily monitored. The eye is also somewhat protected from the body’s immune system, so there is less of an inflammatory response to introduced genes or cells.
The genetic approach
Gene therapy involves using viral vectors to deliver the correct copies of genes into cells that have a defective copy. Much of Robin’s 18 years in gene therapy research have involved perfecting the vectors that deliver the gene; making sure that they target the right cells, for example, and that the gene is switched on at the right level.
Once the vectors had been developed, it was a question of testing the therapies in mouse models of the human diseases. His team have now shown that gene therapy improves vision in around 10 different single-gene disorders in mice, and it’s time to turn their attention to the clinic.
“There’s little more we can learn by treating another mouse. The most exciting science now is in patients and seeing just how effectively the technology can work in people,” says Robin.
In 2007, Robin and his colleagues conducted the world’s first clinical trial of a gene therapy for retinal disease, treating 12 patients for Leber's congenital amaurosis in which children are born with no night vision and gradually lose central vision.
The results showed that gene therapy improved night vision but didn’t impact central vision. The MRC is now funding Robin and his colleagues to improve their viral vector in the hope of being able to sustain central vision too. Alongside this, Robin’s group is applying for regulatory approval to begin clinical trials in other types of retinal degeneration.
Single gene disorders are a good place to show that gene therapy works — and perfect techniques — before moving on to more complex disorders, says Robin.
He’s also interested in gene therapies where the delivered gene codes for a therapeutic molecule, such as molecules that suppress the growth of new blood vessels. These could therefore treat conditions such as age-related macular degeneration, in which blood vessels grow abnormally.
Gene therapy will be useful for patients who still have remaining retinal cells, but Robin is also developing stem cell therapy to replace cells that have already been lost.
This research focuses on two main areas: perfecting the transplantation of retinal precursor cells into mice — and humans — and developing ways of growing a good supply of these from human embryonic stem cells (hESCs). hESCs are the best source, says Robin, because they don’t need much encouragement to become retinal precursors. “Adult stem cells are restricted … it’s hard to push them [down a retinal lineage] while the hESCs have a natural propensity to do so,” he says.
So far, Robin and his colleagues have focused on transplanting rod rather than cone photoreceptor cells, because rods are more abundant in the eye and their precursors are easier to produce when differentiating stem cells.
In 2012 Robin and his colleagues showed that transplanting rod precursor cells —from young healthy mice rather than grown from embryonic stem cells — into the retinas of mice with a type of night blindness can restore their vision. The mice demonstrated enhanced visual responses in the brain and performed better on a task requiring low-light vision.
But getting better at transplanting cones will be key in humans, says Robin, because it is a small number of cones that mediate visual acuity. With a new MRC programme grant, they are now investigating ways to improve cone transplantation in mice.
Robin, along with colleagues at Moorfields Eye Hospital in London, has also recently been involved in the first injection of hESC-derived retinal cells into a patient in Europe. The trial will involve 12 patients with Stargardt disease, a degenerative retinal disease, who will receive hESC-derived retinal pigment epithelium cells — cells which sustain the light-sensing photoreceptors.
The trial is focused on looking at safety rather than whether the transplants improve vision, says Robin. “We’re interested in asking basic questions about safety and delivery, the mechanics of injecting the cells, whether we can visualise them in the eye … We’re unlikely to see any clinical benefit with patients at this stage of disease.”
But that doesn’t mean he isn’t hopeful of the stem cell therapy helping patients one day. “Every now and then there’s just a sudden discovery that comes out of nowhere that just propels things forwards and that’s what’s exciting. Never say never in this field, it’s full of surprises.”
Find out more about the MRC and regenerative medicine.
Published April 2012