The Lancet - 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

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  • 1. ArticlesHuman embryonic stem cell-derived retinal pigmentepithelium in patients with age-related maculardegeneration and Stargardts macular dystrophy: follow-upof two open-label phase 1/2 studiesSteven D Schwartz, Carl D Regillo, Byron L Lam, Dean Eliott, Philip J Rosenfeld, Ninel Z Gregori, Jean-Pierre Hubschman, Janet L Davis, Gad Heilwell,Marc Spirn, Joseph Maguire, Roger Gay, Jane Bateman, Rosaleen M Ostrick, Debra Morris, Matthew Vincent, Eddy Anglade, Lucian V Del Priore,Robert LanzaSummaryBackground Since they were first derived more than three decades ago, embryonic stem cells have been proposed as asource of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewalraises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk ofdifferentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from humanembryonic stem cells (hESC) transplanted into patients.Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety andtolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardtsmacular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dosecohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed upfor a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies areregistered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993(age-related macular degeneration).Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues relatedto 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 retinalpigment 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 theuntreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measuresincreased for general and peripheral vision, and near and distance activities, improving by 1625 points 312 monthsafter transplantation in patients with atrophic age-related macular degeneration and 820 points in patients withStargardts macular dystrophy.Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graftsurvival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our resultssuggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmetmedical disorders requiring tissue repair or replacement.Funding Advanced Cell Technology.IntroductionSince 1981, when pluripotential cell cultures were firstderived by Evans and Kauffman,1 embryonic stem cells(ESC) have been regarded as a potential source oftherapeutic cells for a wide range of diseases causedby tissue loss or dysfunction.2 Despite the greattherapeutic potential, their plasticity and unlimitedcapacity for self-renewal raise concerns about serioussafety issues, including the ability to form teratomasand other tumours, potential immune reactions, andthe risk of differentiating into unwanted cell types.Although ESC have been extensively studied in vitroand in animals for more than three decades, there havebeen no reports of the assessment of their long-termsafety and potential effectiveness in treating humandisease.The use of ESC has been proposed for the treatment ofa wide range of disorders, including myocardialregeneration after myocardial infarction, islet cellreplacement in patients with diabetes, and neural cellreplacement in ischaemic stroke, Parkinsons disease,and Alzheimers disease.2 However, because of itsimmunoprivileged nature (ability to tolerate foreignantigens or non-histocompatible cells without elicitingan immune response), diseases affecting the eye areattractive first-in-human applications for this technology.Published OnlineOctober 15, 2014http://dx.doi.org/10.1016/S0140-6736(14)61376-3See Online/Comment/http://dx.doi.org/10.1016/S0140-6736(14)61820-1Jules Stein Eye Institute RetinaDivision, and David GeffenSchool of Medicine, Universityof California, Los Angeles, CA,USA (Prof S D Schwartz MD,J-P Hubschman MD,G Heilwell MD, R M Ostrick MPH);Wills Eye Hospital and ThomasJefferson University,Philadelphia, PA, USA(Prof C D Regillo MD,M Spirn MD, J Maguire MD);Bascom Palmer Eye Institute,University of Miami, Miami, FL,USA (Prof B L Lam MD,N Z Gregori MD,Prof P J Rosenfeld MD,Prof J L Davis MD);Massachusetts Eye and EarInfirmary and Harvard MedicalSchool, Boston, MA, USA(D Eliott MD); Advanced CellTechnology, Marlborough, MA,USA (R Gay PhD, J Bateman RN,D Morris MPH, M Vincent PhD,E Anglade MD, Prof R Lanza MD);and Storm Eye Institute,Medical University of SouthCarolina, Charleston, SC, USA(Prof L V Del Priore MD)Correspondence to:Prof Robert Lanza, Advanced CellTechnology, Marlborough,MA 01752, USArlanza@advancedcell.comorProf Steven D Schwartz, RetinaDivision, Jules Stein Eye Institute,Los Angeles, CA 90095, USAschwartz@jsei.ucla.eduwww.thelancet.com Published online October 15, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61376-3 1

2. ArticlesThe subretinal space is protected by the blood-ocularbarrier, and is characterised by antigen-specific inhibitionof both the cellular and humoral immune responses.3For locally delivered, intraocular treatments, low dosesare needed compared with systemic therapies, andmeaningful extraocular biodistribution is rare.Degeneration of the retinal pigment epithelium leadsto photoreceptor loss in several sight-threateningdiseases, rendering it an attractive regenerative target.In atrophic age-related macular degeneration, geneticand environmental factors predispose patients toimmune mediated and oxidative stresses that ultimatelycompromise the retinal pigment epithelium. InStargardts macular dystrophy, degeneration of theretinal pigment epithelium is typically induced bygenetically altered photoreceptor outer segments.Respectively, these macular degenerations are two ofthe leading causes of adult and juvenile blindness indeveloped countries. The non-exudative (dry) form ofage-related macular degeneration accounts for 8090%of all cases and is currently untreatable. Similarly, thereare no known treatments to prevent or reverse the lossof vision in patients with Stargardts macular dystrophy.There is evidence that subretinal transplantation ofhESC-derived retinal pigment epithelium can rescuephotoreceptors and prevent visual loss in preclinicalmodels of macular degeneration.4,5 The retinal pigmentepithelium maintains the health of photoreceptorsby recycling photopigments, metabolising andstoringvitamin A, phagocytosing shed photoreceptorsegments, and other functions.6,7 In preclinical models,transplantation of hESC-retinal pigment epitheliumresulted in extensive photoreceptor rescue and improvementin visual function.4 The results of these and otherstudies8 suggest that hESC could be a potentially safesource of retinal pigment epithelium for treatment ofretinal degenerative diseases. Although transplantationof primary retinal pigment epithelium cells has beenattempted in people, the results have been mixed forboth graft survival and visual improvement.916 There areimportant advantages to using cells derived frompluripotent stem cell sources, including the ability tohave a virtually unlimited supply of cells and tocontrol their differentiation to ensure optimum safetyand potency before transplantation. We report themedium-term and long-term results of two prospectiveclinical trials done in the USA to investigate the safetyand tolerability of hESC-derived retinal pigmentepithelium in patients with atrophic age-related maculardegeneration or Stargardts macular dystrophy.MethodsPatients and proceduresFor two phase 1/2 studies in the USA, 18 patients(nine with atrophic age-related macular degeneration andnine with Stargardts macular dystrophy) were selectedfrom four centres in accordance with the inclusion andexclusion criteria, including end-stage disease, genotyping,central visual loss, and absence of other significantophthalmic pathology (appendix). The protocols wereapproved by the institutional review boards and ethicscommittees of the respective sites. Written informedconsent was obtained from all the patients.The hESC and hESC-derived retinal pigment epitheliumcells were generated as previously described.17 Briefly, vialsof hESC-MA09 were thawed, expanded, and differentiatedinto pigmented retinal pigment epithelium patches inaccordance with the current good manufacturing practices.The hESC-retinal pigment epithelium cells were assessedfor safety and characterised for retinal-pigment-epithelium-specificattributes at various times (appendix).Vials of cryopreserved hESC-retinal pigment epitheliumcells were thawed, formulated, Gram stained, anddelivered to the operating room.17 Pars plana vitrectomy,including the surgical induction of posterior vitreousseparation from the optic nerve anteriorly to the posteriorborder of the vitreous base, was done in the eye with theworse vision. 150 L of retinal pigment epithelium wasinjected through a MedOne PolyTip Cannula 23/38 or25/38 (MedOne Surgical, Sarasota, FL, USA), deliveringthe targeted dose of viable retinal pigment epitheliumcells into the subretinal space in sites with a preselectedtransition zone (the area between atrophic photoreceptor,retinal pigment epithelium, and choriocapillaris andfairly healthy post-equatorial retina) as the