ArticlesHuman embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies
Introduction
Since 1981, when pluripotential cell cultures were first derived by Evans and Kauffman,1 embryonic stem cells (ESC) have been regarded as a potential source of therapeutic cells for a wide range of diseases caused by tissue loss or dysfunction.2 Despite the great therapeutic potential, their plasticity and unlimited capacity for self-renewal raise concerns about serious safety issues, including the ability to form teratomas and other tumours, potential immune reactions, and the risk of differentiating into unwanted cell types. Although ESC have been extensively studied in vitro and in animals for more than three decades, there have been no reports of the assessment of their long-term safety and potential effectiveness in treating human disease.
The use of ESC has been proposed for the treatment of a wide range of disorders, including myocardial regeneration after myocardial infarction, islet cell replacement in patients with diabetes, and neural cell replacement in ischaemic stroke, Parkinson's disease, and Alzheimer's disease.2 However, because of its immunoprivileged nature (ability to tolerate foreign antigens or non-histocompatible cells without eliciting an immune response), diseases affecting the eye are attractive first-in-human applications for this technology. The subretinal space is protected by the blood-ocular barrier, and is characterised by antigen-specific inhibition of both the cellular and humoral immune responses.3 For locally delivered, intraocular treatments, low doses are needed compared with systemic therapies, and meaningful extraocular biodistribution is rare.
Degeneration of the retinal pigment epithelium leads to photoreceptor loss in several sight-threatening diseases, rendering it an attractive regenerative target. In atrophic age-related macular degeneration, genetic and environmental factors predispose patients to immune mediated and oxidative stresses that ultimately compromise the retinal pigment epithelium. In Stargardt's macular dystrophy, degeneration of the retinal pigment epithelium is typically induced by genetically altered photoreceptor outer segments. Respectively, these macular degenerations are two of the leading causes of adult and juvenile blindness in developed countries. The non-exudative (dry) form of age-related macular degeneration accounts for 80–90% of all cases and is currently untreatable. Similarly, there are no known treatments to prevent or reverse the loss of vision in patients with Stargardt's macular dystrophy.
There is evidence that subretinal transplantation of hESC-derived retinal pigment epithelium can rescue photoreceptors and prevent visual loss in preclinical models of macular degeneration.4, 5 The retinal pigment epithelium maintains the health of photoreceptors by recycling photopigments, metabolising and storing vitamin A, phagocytosing shed photoreceptor segments, and other functions.6, 7 In preclinical models, transplantation of hESC-retinal pigment epithelium resulted in extensive photoreceptor rescue and improvement in visual function.4 The results of these and other studies8 suggest that hESC could be a potentially safe source of retinal pigment epithelium for treatment of retinal degenerative diseases. Although transplantation of primary retinal pigment epithelium cells has been attempted in people, the results have been mixed for both graft survival and visual improvement.9, 10, 11, 12, 13, 14, 15, 16 There are important advantages to using cells derived from pluripotent stem cell sources, including the ability to have a virtually unlimited supply of cells and to control their differentiation to ensure optimum safety and potency before transplantation. We report the medium-term and long-term results of two prospective clinical trials done in the USA to investigate the safety and tolerability of hESC-derived retinal pigment epithelium in patients with atrophic age-related macular degeneration or Stargardt's macular dystrophy.
Section snippets
Patients and procedures
For two phase 1/2 studies in the USA, 18 patients (nine with atrophic age-related macular degeneration and nine with Stargardt's macular dystrophy) were selected from four centres in accordance with the inclusion and exclusion criteria, including end-stage disease, genotyping, central visual loss, and absence of other significant ophthalmic pathology (appendix). The protocols were approved by the institutional review boards and ethics committees of the respective sites. Written informed consent
Results
In two phase 1/2 studies, nine patients (five female, eight white and one black) were enrolled from July 12, 2011, to Jan 22, 2014, in the Stargardt's macular dystrophy trial and nine patients (six female, all white) were enrolled from July 12, 2011, to Oct 15, 2013, in the age-related macular degeneration trial. The median age was 77 years (range 70–88) in the patients with age-related macular degeneration and 50 years (20–71) in those with Stargardt's macular dystrophy. Transplanted patients
Discussion
Our results show that hESC-derived cells were well tolerated for up to 37 months after transplantation in individuals with atrophic age-related macular degeneration and Stargardt's macular dystrophy. So far, in the two clinical trials, there were no serious adverse safety signals attributed to the transplanted cells. Potential safety concerns about the use of hESC in people, including the possibility of teratoma formation, immune reactions, and the risk of cells differentiating into unwanted
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