Eyes open to stem cells: safety trial may pave the way for cell therapy to treat retinal disease in patients

A clinical trial using human embryonic stem cell (hESC) therapy for an inherited retinal degenerative disease is about to commence. The Advanced Cell Technology (ACT) trial will treat patients with Stargardt's macular dystrophy using transplanted retinal pigment epithelium derived from hESCs. Currently, no effective treatment is available for Stargardt's disease so a stem cell-based therapy that can slow progression of this blinding condition could represent a significant breakthrough. While there are some hurdles to clear, the ACT trial is a fine example of translational research that could eventually pave the way for a range of stem cell therapies for the retina and other tissues.

Th e Medicines and Healthcare Products Regulatory Agency has recently given approval for the fi rst human embryonic stem cell (hESC) clinical trial in the UK. Professor James Bainbridge in partnership with the US company Advanced Cell Technology (ACT) will lead the study at the Moorfi elds Eye Hospital in London. Th e trial is the fi rst of its kind in Europe and will investigate the safety and tolerability of using retinal cells derived from hESCs to treat patients with advanced Stargardt's macular dystrophy. Th is condition is the commonest form of inherited macular degeneration and patients present with central visual loss in their early teens and this is followed by inexorable decline in visual acuity ( Figure 1). Currently, no eff ective treatment is available for Stargardt's disease so a stem cell-based therapy could have a major impact.
Mutations in the gene ABCA4 are responsible for more than 95% of cases of Stargardt's disease [1]. ABCA4 encodes a photoreceptor-specifi c transmembrane protein that transports retinoids from photoreceptors to the retinal pigmented epithelium (RPE). ABCA4 dysfunction results in the deposition of an ageing pigment called lipofuscin in the RPE, which is normally only associated with much older eyes. Reactive chemical components of lipofuscin can damage RPE function and, subsequently, lead to death of photoreceptors. Th e rationale for the proposed intervention in Stargardt's disease is that by replacing damaged RPE with healthy cells, the progression of disease might be signifi cantly halted.
Th e idea of replacing dysfunctional RPE is not novel and diff erent surgical treatments, such as macular translocation or patch graft techniques, have been developed over the past two decades [2][3][4][5]. Th ese surgical tech niques can have severe complications, including prolifera tive vitreoretinopathy, submacular haemorrhage and retinal detachment. Th erefore, a simple subretinal injec tion of replacement RPE derived from hESCs was proposed as an alternative. RPE can be generated from either hESCs or human induced pluripotent stem cells (iPSCs) [6], although it has been reported that hESC-derived cells more closely resemble human primary RPE than cells derived from human iPSCs [7]. In addition, it has also been recently demonstrated that iPSCs maintain an epigenetic memory of the tissue of origin, which can infl uence their directed diff erentiation and function [8]. While RPE diff erentiation effi ciency may vary between hESC lines, experimental data using animal models with photoreceptor degeneration have shown that trans planted human cells integrate into the host RPE layer with no tumour formation [9]. Importantly, RPE cellular replacement therapy signifi cantly improves vision in treated animals when compared to untreated controls [9]. How this occurs is still not completely certain and there are confl icting data regarding trans planted cell survival and whether they fully integrate into the RPE monolayer or aggregate in clumps [10]. It is also possible that benefi ts of this cell therapy are actually due to a concomitant nonspecifi c paracrine eff ect or immune response rather than the injected cells acquiring a specifi c RPE phenotype and functioning as such.

Abstract
A clinical trial using human embryonic stem cell (hESC) therapy for an inherited retinal degenerative disease is about to commence. The Advanced Cell Technology (ACT) trial will treat patients with Stargardt's macular dystrophy using transplanted retinal pigment epithelium derived from hESCs. Currently, no eff ective treatment is available for Stargardt's disease so a stem cell-based therapy that can slow progression of this blinding condition could represent a signifi cant breakthrough. While there are some hurdles to clear, the ACT trial is a fi ne example of translational research that could eventually pave the way for a range of stem cell therapies for the retina and other tissues.
Th erefore, the recent announcement of the ACT trial on patients with Stargadt's disease is timely and the balance between risks and benefi ts will be carefully evaluated. Results from this ACT clinical trial ought to address some critical questions regarding hESC-based therapies in the eye. Will the transplanted hESC-derived RPE carry a risk of tumour formation? Will there be an immunological response by the retina from non HLAmatched foetal RPE? Will immunosuppressants be required?
While stem cell therapy holds promise for regenerating many cells and tissues, the retina can be regarded as an ideal test-bed for cell therapies. It is easily accessible and transplanted cells can be readily visualised during the surgery, visual function can be accurately measured, and complications can often be identifi ed early and addressed with local treatment. Th is trial will be recruiting only patients with advanced macular degeneration in order to protect against potential adverse events on visual function. Th is will clearly limit the question of effi cacy as there might be a window of opportunity for the cell therapy to be clinically benefi cial. For example, if patients' disease is very advanced, then photoreceptor degeneration and RPE dysfunction might not be salvageable. Other similar issues related to advanced disease are changes in RPE substrate (known as Bruch's membrane) and a pro-infl ammatory tissue microenvironment could have a negative impact on the effi cacy of the cell therapy. Th erefore, if this phase I/II ACT trial proves to be safe, further phase III/IV trials to focus on treatment effi cacy are warranted. Indeed, since Stargardt's disease shares some important features with age-related macular degeneration, advances made in the ACT study could provide hope for cell therapy in the treatment of this, the most common cause of blindness in the Western world.
Considering all recent advances in cellular and molecular biology, biotechnology, nanotechnology, and immunology, this ACT trial represents the beginning of a new era for stem cell research and translational science. With particular reference to retinal disease, this exciting study could provide meaningful information to guide and encourage the development of other cell therapies that can promote blood vessel regeneration in ischaemic retina, neuronal survival or synaptic reconnection of transplanted photoreceptor precursors.