Human 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

Summary

Background

Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.

Methods

In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration).

Findings

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt's macular dystrophy.

Interpretation

The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.

Funding

Advanced Cell Technology.

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.