Gene and cell therapies for age-related macular degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of sight loss amongst the elderly. Find out about how you can support our work and help develop more effective therapies.


Existing therapies for AMD target the damaging growth of blood vessels from the choroid - a process known as choroidal neovascularisation (CNV) that is responsible for the "wet" form of AMD. These require monthly injections into the eye and can cause harmful side-effects.

There are currently no effective treatments for the "dry" form in which sight progressively deteriorates. We are developing two types of therapy to prevent or reverse sight loss in AMD, based on a research programme that furthers our understanding of how sight is lost in AMD.

Gene therapy for AMD

Controlling the damaging growth of leaky blood vessels in 'wet' AMD

We have found that it is possible to control the harmful growth of leaky blood vessels using genes delivered to the retina by viral vectors (Balaggan et al Gene Therapy 2006Surace et al Mol Ther 2006). Such treatments are promising because the genes delivered could provide protection in the long-term without the need for repeated injections.

Clinical trials of gene therapy for the treatment of CNV, based in part on our proof of concept studies, are being carried out by other groups in the United States. We aim to start our own clinical trial in the future in the UK.

Cell transplantation and stem cell therapy to repair the retina in AMD

Transplanting RPE cells derived from stem cells to repair damage in AMD

Both "wet" and "dry" forms of AMD lead to the loss of retinal pigment epithelium (RPE) cells, which support the light-sensitive photoreceptor cells of the retina.

Our current clinical trial testing the safety and efficacy of stem cell transplantation to repair the RPE is focusing on people with advanced sight loss due to Stargardt macular dystrophy.

Should this trial indicate that transplanting stem cell-derived RPE cells is safe, and further studies show that sight can be restored, a similar procedure could help restore vision in AMD.

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

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.

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).

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 geneticall 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)

The successful transplantation of cone photoreceptor cells is particularly important for a cell therapy targeting AMD, as the macula has the highest concentration of cone cells.

Publications on gene and cell therapy for inherited sight loss


Understanding AMD

AMD is a complex disease where central vision is damaged by a combination of genetic and environmental factors - although some genetic changes can increase your chances of developing AMD, the most important risk factors are age, smoking, diabetes and high blood pressure.

Early AMD is characterised by the appearance of yellow deposits in the retina, called drusen. Early AMD can develop into two forms of advanced disease - the 'dry' form, where large parts of the retinal pigment epithelium (RPE) and some light-sensitive photoreceptor cells are lost from the retina, or the 'wet' form, where the growth of abnormal growth of leaky blood vessels damages the retina and causes sight loss.

We have a programme of laboratory research investigating the mechanisms involved in sight loss due to AMD.


Understanding AMD - the role of oxygen in sight loss

We are investigating the role of oxygen in AMD (Lange et al 2012), as disturbances to the delivery and usage of oxygen are an important factor in the damaging growth of new blood vessels. We have shown that a molecule that helps regulate how cells respond to a lack of oxygen, known as HIF-1, plays a crucial role in the growth of abnormal and leaky blood vessels (Mowat et al 2010). Together these results show the important role that the control of oxygen levels in the retina plays in diabetic eye disease as well as in AMD and may help identify new drug targets.

Understanding AMD - the role of the immune system

Research indicates that the immune system plays a significant role in AMD. Genetic variation in genes that make up the immune system are associated with a greater risk of AMD.

We are evaluating animal models in order to study how different components of the immune system contribute to different features of AMD (Luhmann et al, PLoS One, 2012). We are also developing new models to further our understanding of AMD. This research will advance our understanding of how age and other factors lead to sight loss in AMD, and help us identify new drug targets and gene therapy strategies.

Page last modified on 28 may 13 12:28


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