Embryonic stem cell trials for macular degeneration: A preliminary report

Jules Stein Eye Institute Retina Division, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
The Lancet (Impact Factor: 45.22). 02/2012; 379(9817):713-20. DOI: 10.1016/S0140-6736(12)60028-2
Source: PubMed


It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients.
We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration--the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with, numbers NCT01345006 and NCT01344993.
Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).
The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.
Advanced Cell Technology.

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    • "NCT01345006) received subretinal injections of retinal pigment epithelium cells derived from human ESCs. Twenty-two months of follow up revealed that visual acuity improved significantly in 10 of 18 patients and to a lesser extent in the next seven patients (Schwartz et al. 2012). Currently, several other clinical trials based on PSC transplantation are ongoing (; "
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    ABSTRACT: Pluripotent stem cells (PSCs), such as embryonic stem cells or induced pluripotent stem cells are a promising source of cells for regenerative medicine as they can differentiate into all cell types building a mammalian body. However, protocols leading to efficient and safe in vitro generation of desired cell types must be perfected before PSCs can be used in cell therapies or tissue engineering. In vivo, i.e. in developing mouse embryo or teratoma, PSCs can differentiate into skeletal muscle, but in vitro their spontaneous differentiation into myogenic cells is inefficient. Numerous attempts have been undertaken to enhance this process. Many of them involved mimicking the interactions occurring during embryonic myogenesis. The key regulators of embryonic myogenesis, such as Wnts proteins, fibroblast growth factor 2, and retinoic acid, have been tested to improve the frequency of in vitro myogenic differentiation of PSCs. This review summarizes the current state of the art, comparing spontaneous and directed myogenic differentiation of PSCs as well as the protocols developed this far to facilitate this process.
    Full-text · Article · Dec 2015 · Journal of Muscle Research and Cell Motility
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    • "Please cite this article in press as: Plaza Reyes et al., Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model, Stem Cell Reports (2016), ongoing clinical studies (Schwartz et al., 2012). Moreover, we demonstrate that suspension transplantations of rhLN-521-hESC-RPE integrate as polarized subretinal monolayers that rescue overlying photoreceptors from induced damage. "
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    ABSTRACT: Human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells could replace lost tissue in geographic atrophy (GA) but efficacy has yet to be demonstrated in a large-eyed model. Also, production of hESC-RPE has not yet been achieved in a xeno-free and defined manner, which is critical for clinical compliance and reduced immunogenicity. Here we describe an effective differentiation methodology using human laminin-521 matrix with xeno-free and defined medium. Differentiated cells exhibited characteristics of native RPE including morphology, pigmentation, marker expression, monolayer integrity, and polarization together with phagocytic activity. Furthermore, we established a large-eyed GA model that allowed in vivo imaging of hESC-RPE and host retina. Cells transplanted in suspension showed long-term integration and formed polarized monolayers exhibiting phagocytic and photoreceptor rescue capacity. We have developed a xeno-free and defined hESC-RPE differentiation method and present evidence of functional integration of clinically compliant hESC-RPE in a large-eyed disease model.
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    • "The transplantation of RPE cells prevented the progression of photoreceptor and visual loss in various animal models. However, attempts to transplant new RPE cells into diseased eyes of human AMD patients have been challenging (Algvere et al., 1994, 1997, 1999; Binder et al., 2002, 2004, 2007; Tezel et al., 2007; Falkner-Radler et al., 2011; Schwartz et al., 2012), and only resulted in improved vision in a limited number of cases (Heller and Martin, 2014). "
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    ABSTRACT: Diseases such as age-related macular degeneration (AMD) affect the retinal pigment epithelium (RPE) and lead to the death of the epithelial cells and ultimately blindness. RPE transplantation is currently a major focus of eye research and clinical trials using human stem cell-derived RPE cells are ongoing. However, it remains to be established to which extent the source of RPE cells for transplantation affects their therapeutic efficacy and this needs to be explored in animal models. Autotransplantation of RPE cells has attractions as a therapy, but existing protocols to isolate adult RPE cells from rodents are technically difficult, time-consuming, have a low yield and are not optimized for long-term cell culturing. Here, we report a newly devised protocol which facilitates reliable and simple isolation and culture of RPE cells from adult rats. Incubation of a whole rat eyeball in 20 U/ml papain solution for 50 min yielded 4 × 104 viable RPE cells. These cells were hexagonal and pigmented upon culture. Using immunostaining, we demonstrated that the cells expressed RPE cell-specific marker proteins including cytokeratin 18 and RPE65, similar to RPE cells in vivo. Additionally, the cells were able to produce and secrete Bruch’s membrane matrix components similar to in vivo situation. Similarly, the cultured RPE cells adhered to isolated Bruch’s membrane as has previously been reported. Therefore, the protocol described in this article provides an efficient method for the rapid and easy isolation of high quantities of adult rat RPE cells. This provides a reliable platform for studying the therapeutic targets, testing the effects of drugs in a preclinical setup and to perform in vitro and in vivo transplantation experiments to study retinal diseases.
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