A A A

Eye Therapy News

2 Lazy 2 Run? We’re biking it for blood cancer!

Fri, 29 Aug 2014 09:30:05 +0000

  On Sunday 31 August a group of not so elite athletes from the Gene and Cell Therapy group will be taking part in the London Bikeathon 2014 to raise funds for Leukaemia & Lymphoma Research. The 2 Lazy 2 Run CC will be cycling 52 miles – that’s more than a marathon, no mean feet […]

Read more...

The Art of Eyes

Thu, 07 Aug 2014 14:23:19 +0000

The eye is an object of great beauty as shown by the Ophthalmologist in their July/August 2014 issue. This month’s issue features a photo essay called The Art of the Eyes and includes examples of the work from a number research labs capturing the complex and beautiful detail of the eye and its cells. The essay includes images […]

Read more...

In memoriam

Tue, 05 Aug 2014 16:02:34 +0000

Dr Yoshiki Sasai (1962 – 2014) It is with great sadness today that we remember and pay tribute to our collaborator Dr Yoshiki Sasai. Yoshiki was a world leading stem cell researcher and Deputy Director of the Riken Center for Developmental Biology in Kobe, Japan. Through his hard work and dedication over many years, Yoshiki […]

Read more...

International Clinical Trials Day: Our Work in Summary

Tue, 20 May 2014 15:03:41 +0000

Introduction Today, 20 May 2014, is International Clinical Trials Day. This landmark day remembers the pioneering work of James Lind a Scottish naval physician who, in the 1700s, conducted the first controlled clinical study that identified that citrus fruit (containing Vitamin C) was effective in treating scurvy. Each year, a number of organisations mark this […]

Read more...

Gene and cell therapies for inherited sight loss

Inherited sight loss affects around 1/3000 people and there are no treatments available. Find out about how you can support our work and help develop effective therapies.


We are developing a pipeline of potential treatments, having established proof-of-concept that both gene therapy and the transplantation of stem cell-derived retinal cells can effectively restore vision in small and large animal models of inherited sight loss.

Gene therapy for inherited sight loss

Leber congenital amaurosis (LCA) caused by mutations in RPE65

LCA is an severe, early-onset form of retinal degeneration in which peripheral and night vision is lost from the first decade of life, followed in most cases by central, daytime vision. Although it is a rare condition, affecting around 1/80,000 people, LCA is thought to account for around 1/5 cases of childhood blindness and there is no treatment currently available.

We have developed gene therapy for LCA caused by damage to the RPE65 gene, which is found in the retinal pigment epithelium cells that support the light-sensitive photoreceptor cells of the retina. Mutations in RPE65 are thought to cause around 8% of LCA cases.

With proof-of-concept for RPE65 gene therapy established in models of disease, we are testing this therapy in our first-in-man clinical trial of gene therapy for LCA caused by mutations in the RPE65 gene. Results from this trial indicate that gene delivery using viruses is well tolerated and is able to improve vision (Bainbridge et al. NEJM 2011).



Further trials will help determine whether improvements to vector design can enhance the beneficial effect of RPE65 gene therapy on sight.

Leber congenital amaurosis (LCA) caused by mutations in AIPL1

LCA is an severe, early-onset form of retinal degeneration in which peripheral and night vision is lost from the first decade of life, followed in most cases by central, daytime vision. Although it is a rare condition, affecting around 1/80,000 people, LCA is thought to account for around 1/5 cases of childhood blindness and there is no treatment currently available.

We have shown that treating mice with sight loss caused by damage to the AIPL1 gene, by delivering a working copy of AIPL1, restores structure and function to both rod and cone photoreceptor cells. We have also demonstrated that this gene replacement therapy can prevent the loss of photoreceptor cells from the retina - this means that gene replacement therapy for AIPL1 is one of the most robust therapies to be tested in models of inherited retinal degenerations.

We are planning to start a clinical trial for patients with LCA caused by damage to the AIPL1 gene.

Gene therapy rescues mouse model of inherited blindness
We are planning a clinical trial for patients with the AIPL1 form of LCA (changes to the retina in AIPL1 LCA are shown in the left panel), having shown that gene delivery using AAV restores vision in a model of disease (right panel shows that gene delivery restores AIPL1, coloured green, to the light-sensitive photoreceptor cells - which also correctly house the machinery needed to detect light, coloured red here)

Achromatopsia caused by mutations in CNGB3

Achromatopsia is a rare, recessively inherited condition affecting around 1/30,000 people in which colour vision is completely lost, central detailed vision is distorted and patients experience extreme light sensitivity. Currently there is no treatment available although some symptoms may be lessened by wearing red contact lenses and dark wrap-around glasses.

Damage to the CNGB3 gene is associated with around 50% of achromatopsia cases. We have demonstrated that delivering a working copy of the CNGB3 gene can restore vision in a model of achromatopsia lacking CNGB3 - our study showed long-term restoration of sight and included improvements to the ability of treated mice to track a visual stimulus.

AAV gene therapy improves cone photoreceptor cell survival in model of achromatopsia caused by mutation in CNGB3
AAV gene therapy improves cone photoreceptor cell survival in model of achromatopsia caused by mutation in CNGB3. Compared with untreated (top right, bottom right), AAV.CNGB3 gene therapy restores CNGB3 protein (top left) and the light-sensitive opsin pigment (bottom left) to cone photoreceptor cells

We are planning to conduct a clinical trial testing the delivery of the CNGB3 gene to patients with achromatopsia using an AAV vector.

Leber congenital amaurosis (LCA) caused by mutations in RDH12

Ongoing research shows that gene therapy in a mouse that lacks RDH12 can restore the biochemical pathway that is responsible for sight loss in this form of LCA.

We are planning a clinical trial to test the safety and efficacy of delivering the RDH12 gene to patients with LCA.

X-linked Retinitis pigmentosa (RP) caused by mutations in RPGR

X-linked RP is caused by damage to one of two genes; the form associated with mutations in the RPGR gene causes 14% of RP cases making it the commonest cause of retinitis pigmentosa. Patients usually experience loss of peripheral vision and reduced central vision by the age of 20, accompanied by significant changes to pigmentation in the retina that are characteristic of RP.

AAV gene therapy rescues photoreceptor cells damaged due to X-linked RP
Damage to the RPGR gene causes X-linked RP, causing pigmentary changes in the retina (top panel) and loss of sight from an early age. AAV gene therapy rescues cone photoreceptors in a model of X-linked RP lacking RPGR, restoring RPGR protein (middle right panel) and cone opsin pigment (bottom right panel) compared with untreated (middle and bottom left panels)

With proof-of-concept for gene replacement being established in animal models of disease, we are now planning clinical trials to test the safety and efficacy of RPGR gene delivery using AAV in patients.

Leber congenital amaurosis (LCA) caused by mutations in RetGC-1

LCA is an severe, early-onset form of retinal degeneration in which peripheral and night vision is lost from the first decade of life, followed in most cases by central, daytime vision. Although it is a rare condition, affecting around 1/80,000 people, LCA is thought to account for around 1/5 cases of childhood blindness and there is no treatment currently available.

We have demonstrated long-term improvements in vision following the delivery of the RetGC-1 gene (also known as GUCY2D) using AAV in a model of LCA. Treatment leads to increased survival of cone photoreceptor cells and improvements in electrical activity of the retina as measured by ERG.

Gene therapy restores RetGC-1 protein
Gene therapy restores expression of RetGC-1 protein, shown here in green, in a model of LCA in which RetGC-1 is missing

We are in the early stages of planning a clinical trial for this condition, which would test the safety and efficacy of delivering the RetGC-1 gene to patients with LCA caused by damage to that gene.

Dominant retinitis pigmentosa (RP) caused by mutations in Prph2

A disease such as RP is inherited dominantly when damage to just one copy of a gene is enough to significantly alter the function of cells and cause disease. In such cases gene replacement therapy is unlikely to provide benefit – we need to silence the mutant gene, and in most cases would need to supply a working copy of the gene that isn’t silenced alongside – this approach is known as ‘suppression-replacement therapy.’

RNA interference (RNAi) is a naturally-occurring process in which small RNA molecules silence specific genes by binding to them and initiating their breakdown by the cell.

We have shown that RNAi delivered by rAAV vectors can effectively silence the expression of Peripherin-2,  which is damaged in both autosomal dominant retinitis pigmentosa and dominant maculopathies.

Gene therapy for retinitis pigmentosa
RNA interference can silence the Peripherin-2 gene (shown in the right panel with a reduction in green staining for the Peripherin protein), which is damaged in dominant retinitis pigmentosa (left panel shows the changes to pigmentation in the retina of a patient with dominant RP)

We are now applying a suppression-replacement approach to models of disease in which mutations in Peripherin-2 cause dominant retinal degeneration, and investigating how RNA interference could be applied to other models of dominant disease.

Developing further gene therapy strategies for inherited retinal degeneration

Gene supplementation strategies

Our programme of gene therapy research includes many more proof-of-concept studies, showing that several other forms of inherited retinal degeneration may benefit from gene supplementation therapy - delivering a working copy of a gene that is damaged in disease.

We have shown that retinal cell structure and function is improved following viral gene delivery in models of inherited sight loss caused by mutations in the following genes:

Neuroprotection - preventing retinal cell loss

We have studied the delivery of genes encoding growth factors to photoreceptor cells, in a strategy called neuroprotection. This strategy aims to prevent photoreceptor cells from being lost, and is designed to be used as a more general therapy alongside specific gene replacement treatments.

Our studies show that although neuroprotection (the delivery of growth factor genes) can prevent cell loss in models of disease, in some cases it can also cause damage to photoreceptor cell function (this is particularly the case with a gene called CNTF). We also showed that an alternative growth factor, GDNF, can enhance the effects of gene replacement therapy in models of inherited retinal degeneration without causing the damaging side effects seen with CNTF.

More publications on gene and cell therapy for inherited sight loss


Cell transplantation and stem cell therapy for inherited sight loss

In the advanced stages of inherited diseases like RP and LCA, the light-sensitive photoreceptors are lost, which means that gene therapy is unlikely to be effective. It may be possible to repair the retina by replacing the lost photoreceptor cells using the transplantation of cells derived from stem cells.

We have made important breakthroughs regarding cell transplantation therapy for retinal repair.

Transplanting immature photoreceptor cells can effectively repair the degenerating retina

In a landmark study we showed that immature photoreceptor cells integrate with the host retina when transplanted into models of inherited retinal degeneration, provided they are at the correct stage of development.

Integrated photoreceptor cells connect with host retina
If donor cells are taken from the right stage of retinal development, they can repair a damaged retina when transplanted. They show all the features of mature photoreceptor cells (left panel), including the machinery needed to detect light and connections with other retinal cells (right panel)

Cells that are too early in development, or adult cells, fail to integrate as efficiently - this means that immature photoreceptor cells are the best source of donor cells for transplantation.

We have also shown that manipulating the retina that is to receive such cell transplants can improve the number of integrated cells

Cell transplantation can improve vision in animals with impaired sight

Having shown that cell transplants can repair the degenerating retina, we demonstrated the restoration of vision following transplants - this breakthrough study provides the first evidence that vision-guided behaviour can be effectively restored using the transplantation of immature photoreceptor cells.


Generating retinal cells for transplantation from stem cells

The efficient transplantation of photoreceptor cells requires donor cells to be at a precise stage in retinal development. It would not be possible to obtain such cells from humans as this stage of development corresponds to the second trimester of pregnancy. Therefore the challenge is to generate sufficient cells that are suitable for transplant in a dish, and the best sources for obtaining such cells are embryonic stem cells or adult cells reprogrammed to become stem cells (induced pluripotent stem, or iPS, cells).

Following the discovery that embryonic stem cells can spontaneously develop into retinal cells if placed in the right conditions in a three-dimensional culture system, we have shown that we can recreate eye development and produce retinal cells for transplantation.

Retinal cells spontaneously develop from embryonic stem cells in 3D culture
Retinal cells spontaneously develop from embryonic stem cells in 3D culture. Four panels show cells grown from embryonic stem cells expressing different proteins found in photoreceptor cells

A similar strategy is being used by Advanced Cell Technologies (ACT) to produce retinal pigment epithelium cells from human embryonic stem cells, which we are transplanting into patients with Stargardt macular dystrophy in Europe's first safety trial of embryonic stem cell-derived cells.

Transplanting cone photoreceptor cells

The photoreceptor cell transplantation studies carried out to date have mostly used immature rod photoreceptor cells, as theses are the easiest to study in a mouse system.

For a clinical photoreceptor transplant treatment to be effective, it is important to develop ways to transplant cone photoreceptor cells too. We have shown that when a mix of immature rod and cone photoreceptors are transplanted, we can see mature cone cells integrating into the recipient retina (Lakowski et al Hum Mol Genet 2010).

Integrated cone photoreceptor cells
Cone photoreceptors that are genetically labelled with Green Fluourescent Protein (GFP, top panel) can integrate with host retina when isolated and transplanted - they also produce proteins found in mature cone photoreceptors cells (bottom panel)


Page last modified on 30 nov 12 10:54