Restoring Sight

At University College London's Institute of Ophthalmology, Dr Rachael Pearson and her team are developing ways to restore sight to the blind, by replacing damaged photoreceptors in the eye. Kat Arney started by asking her why we can't just grow new photoreceptors ourselves.

Rachael -   The problem with most neuronal cells, certainly in mammals including humans, is that we're very bad at regenerating our neurons and that goes to the photoreceptors as well.  So, once they've degenerated, once they've died, we're not able to replace them.  There are certainly other animals that can regenerate.  So for example, fish and a lot of the lower vertebrates.  So frogs, fish, newts, all of those sorts of animals have an amazing capacity to regenerate.  In the case of the eye, you can ablate large areas of the eye and they will actually grow a new retina.

Kat -   You can poke them in the eye and it will grow back.

Rachael -   You can poke them in the eye and they'll get a new one.  Sadly, it's not the same for us.  We're much worse at doing that.

Kat -   If we can't grow back our photoreceptors, how are you and your team trying to counteract some of this degeneration that happens?

Rachael -   So, there are various strategies that are being looked at obviously.  One is that you try and get in there first and you correct the genetic defects - that would be gene therapy.  And then there are cell therapy strategies which is the idea that we've lost those cells.  Can we put them back?  Can we find a suitable cell type that will do the same job?  And then related to that is, could we actually try and persuade our own retina to regrow and repair itself? 

But coming back to the cell based therapies, which is the area that I'm primarily working on at the moment, we're interested in trying to identify appropriate sources of donor cells that we can literally, physically transplant back into the patient's eye.  And then the hope is that those cells would then migrate to the right place, they turn into the right cell that we're interested in - the photoreceptor. But then they also need to do quite a few other things.  They need to wire up.  They need to form new connections to those next cells in line and they need to be able to detect light and pass those signals on.

Kat -   Where are you with this kind of research?  What have you done so far?

Rachael -   All of the work to date is still very much in the preclinical stages.  We're not at the clinical trial stage yet.  But what we have managed to do is demonstrate that it's possible to take cells from one eye and you essentially dissociate them.  If you turn them into single cells, you're not putting a piece of tissue in.  but you can immature cells from a developing retina and you can dissociate them into single cells and then transplant those into the back of the eye of a recipient animal.  That recipient has a retinal degeneration so its photoreceptors are dying. 

If you transplant those cells and these cells manage to migrate into the degenerating retina, they can turn into the right cell type into the photoreceptors and they can also form new connections.  We've then been able to go on to show that those cells are able to function as a normal photoreceptor so they are light sensitive.  They detect light and they turn this into an electrical signal.  This signal is then passed down both through the retina, but then also, all the way up to the brain.

Kat -   Sounds good.

Rachael -   It sounds good.  It is good.  It's very encouraging.  So, that's where we've got on that side.  One of the issues with it is that those cells that we identified as being really good at doing this come from a period in development that would make it very difficult for us to translate into the human situation, because it comes during the equivalent in humans would be towards the end of the first trimester, second trimester.

Kat -   This is foetal tissue?

Rachael -   So, this would've then be in foetal tissue which obviously has ethical and practical implications.  So, we want to then think about alternative donor cells.  And so, that's then led us onto stem cells themselves.  We're now trying to take embryonic stem cells and basically grow eyes in a dish.

Kat -   These are the stem cells from the very, very earliest time of development where you have a little ball of cells when they first start get going.  How do you then turn them in a dish into these photoreceptor cells?

Rachael -   That would be giving the secrets away.  Essentially, what you're trying to do is recapitulate normal eye developments.  We're very lucky working in the eye because it's a wonderful model and it's been studied for many, many years.  So, we actually know a lot about how the eye normally develops.  We know a lot about the signalling pathways that turn - a cell that could grow and be an eye or equally, it could grow a liver and kidney or anything else.  We know what the signals are during embryonic development that say actually, "No, good.  Don't do that.  Go and be an eye or go and be a cell within the eye." 

And so, we're able to start to use these and introduce the same signalling pathways in the culture dish.  So, we're trying to stepwise turn this cell from being an undifferentiated embryonic stem cell into a cell that knows it's going to become a retinal cell and then more specifically, it knows it's going to become of these photoreceptors that we have found to be really good for transplanting.

Kat -   And that's using embryonic stem cells which still you'll require source of embryos for them.  Is there any interest in using the new kind of reprogrammed stem cells, the inducible pluripotent stem cells we hear so much about?

Rachael -   Absolutely, there's interest in those.  We're investigating them as well.  We're very interested to understand their potential.  They have the advantage that obviously, you could take them from an autologous source, which means it's coming the patient themselves.  So, you remove the ethical issues associated with embryonic stem cells.  The problem with those obviously is that an IPS cell, if it comes from a patient with a genetic mutation that causes retinal degeneration, any cell that we turn into retina from that patient will still have that retinal degeneration. 

So, we can make new photoreceptors but they will still be affected in the same way.  We have to think about that when we're using IPS cells and we may need to go and correct that genetic defect in vitro before we use those cells for cell transplantation.  So, it's not completely straightforward to use an IPS cell.  But they're still very interesting sources.  I think at the moment, the field is at a point where we still need to investigate both and look to see the relative pros and cons of both of them.

Kat -   With the kind of the molecules, the pathways you're discovering that turn embryonic stem cells into photoreceptors, are there similar pathways that could be reactivated within the eye to make new photoreceptors grow in situ in the eyeball?

Rachael -   Yeah.  That's a really interesting strategy and it's one that I'm interested in.  I think it's still very much in its infancy at the moment as an idea.  So, there is the idea at the moment that there's a population of cells called monoglial cells and these are support cells in the eye.  They in lower vertebrates can de-differentiate, which means they can kind of take step back with developmentally.  They can become these cells that proliferate to generate new neurons and they can help also at the repair process.  So, the idea might be that in humans, maybe we can do the same thing.  We don't know yet, but the idea is that we might be able to turn these smaller cells back a step and allow them to re-enter the cell cycle and generate new photoreceptors.  But that's very much at its infancy at the moment.

Kat -   It sounds like there a lot of interest, a lot of excitement, a lot of ideas, but presumably also some very big challenges.  What do you see is maybe the key challenge that needs to be overcome if you can pick one to really take this forward?

Rachael -   As you said, there are many challenges.  And so, it's tough to know which one is going to be the defining one.  I think at the moment, so much of our work has been based on animal models and particularly on the rod transplantation.  So, as I mentioned those are the ones that we're interested in that we use to detect low light levels.  For us as humans, obviously, the really important things are cones.  We rely so heavily on our vision to navigate during the day.  I think the most important challenge really is to know whether or not this strategy would work for cones.  So, that's something that we're putting an awful lot of time and effort into at the moment and trying to see if we can transplant cones and restore cone mediated vision.

Kat -   It must be really fantastic when you could see that you can transplant these cells and that they will work, and that they will send signals.  It's difficult to cast too far into the future, but it's really nice to think of maybe in sort of 15, 20 years' time that there are viable cell therapies.  That would be great.

Rachael -   It will be great.  It will be absolutely amazing and that's obviously what keeps all of us going.  We really do hope that this strategy will come to fruition.