How gene therapy can cure eye disease

Avalanche Biotechnologies is one of the World Economic Forum’s 2015 class of Technology Pioneers. The company is developing gene therapies to treat eye diseases. Co-founder Tom Chalberg discusses the development of the technology and possible future applications.

Are eye diseases particularly suited to a gene therapy approach?

The eye does have some advantages for gene therapy compared to some other parts of the body. It’s a very small area to treat – just 2.5 square millimetres of the retina is responsible for a tremendous amount of visual function, which in turn has an enormous impact on people’s quality of life. Being also in an enclosed space, it enjoys some degree of immune privilege, that is, the immune system is kept away from potentially negating the effect of the therapy.

The cells are relatively accessible, using common ophthalmological techniques. And we also have the advantage of having really good endpoints, or ways to tell how well we’re succeeding – there are many tests of how well someone’s vision is working.

What is wet AMD and how do you treat it?

AMD, or age-related macular degeneration, is a disease that affects the part of the eye responsible for central vision, that is, what you see directly in front of you. There are two types – “dry” and “wet” – of which wet is the less common, but more serious. It involves blood vessels invading the space between layers of cells in the retina and leaking fluid, and it can lead to severe vision loss. Every year about 150,000 to 200,000 people develop wet AMD in the United States alone. Without treatment, about half of them would be blind or partially sighted within three years.

There is a treatment for wet AMD, but it requires patients to have an injection in their eye every four to eight weeks. Clearly it would be better if they could have just one injection and forget about it. What we hope to do is to set up a kind of factory inside the patient’s eye that will churn out a protein that stops the blood vessels from growing. To do this, we are experimenting with viruses and replacing some of its genes so that it works like a Trojan horse. We then inject the virus with the new gene into the retina. We are looking to see if the virus can get to specific cells in the patient’s own retina to produce the protein that blocks blood vessel growth.

What else is in the pipeline?

We’re developing therapies for an inherited retinal disease caused Juvenile X-linked Retinoschisis, and for colour vision deficiency. The most common form of this, red-green colour blindness, affects a very large number of people – about 10 million in the United States alone. There are also rarer, more severe forms.

What links all forms of colour vision deficiency is that patients are missing a gene responsible for making a photopigment. Most humans have three of these receptors in the retina, in each of the primary colours, and the colours we experience are a mix of the signals they send to the brain. People with colour vision deficiency are missing one or more photoreceptor, so they have a very limited colour sensation – they can see just a small fraction of colours most humans can see. And that can be very limiting for certain professions – the military, pilots, electricians and so on.

So the idea is to use gene therapy to reintroduce the missing photopigment. That’s currently in preclinical testing, and we hope to move to human trials in a year or two.

Looking further ahead, where do you imagine the technology being in 10 or 20 years?

One reason we’re so excited about our progress on colour vision deficiency is that we’ve learned how to get much better at specifically accessing cone photoreceptors – one of the several types of cell in the multiple layers of the retina. Different cell types are involved in different types of blindness. For example, retinal ganglion cells are involved in glaucoma, RPE cells in macular degeneration, and rods and cones are involved in a whole list of genetic diseases.

Over the next decade or two, we expect to get much better at targeting these specific cell types in the retina by developing a new generation of viral vectors, through a process we call directed evolution. When you think about it, viruses evolved over millions of years to perform specific functions, and it would be surprising to discover that nature had made a virus that just so happened to be optimally adapted to go into the retina, find a certain cell and create a therapeutic protein. We are creating viral vectors that are not naturally occurring, making large libraries of them and running multiple rounds of selection to find those which can do specific jobs more effectively.

The better we get at creating new, non-naturally occurring vectors that can effectively target each of these cell types, the more able we will be to develop therapies for a whole range of eye conditions.

Full details on all of the Technology Pioneers 2015 can be found here. 

Author: Tom Chalberg, Co-founder, Avalanche Biotechnologies, a World Economic Forum Technology Pioneer.

Image: A doctor checks the eyes of a child at the Tambora community health centre in Jakarta March 29, 2011. REUTERS/Beawiharta