Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

“…High dose rapamycin is known to elicit unwanted side effects, so it is unfortunate that such high dosage trials have been designed and conducted, with negative outcomes, as they are likely to reinforce clinical prejudice against use of mTOR inhibitors for non-life-threatening illness. Full dose-response trials to obtain maximal benefit with minimal side effects are still needed, particularly as AMD treatment options are limited and pharmacological therapies should provide a cheaper and more accessible option to the successful stem cell treatments recently reported [154]. …”

How human embryonic stem cells sparked a revolution

“…There have been at least six clinical trials, in the United States, the United Kingdom, South Korea, China and Israel. On 19 March, researchers led by ophthalmologist Pete Coffey, director of the London Project to Cure Blindness and the University of California, Santa Barbara, reported the results of a study to implant a patch of cells made from ES cells into the damaged retinas of two individuals 2 . A year after the procedure, the participants regained the ability to read, albeit slowly.…”

“…Starting with an attempt to repair spinal-cord injuries in 2010, there have been more than a dozen clinical trials of cells created from ES cells -to treat Parkinson's disease and diabetes, among other conditions. Early results suggest that some approaches are working: a long-awaited report this week shows improved vision in two people with age-related macular degeneration, a disease that destroys the sharpness of vision 2 . "In some ways, it's not a surprise, because 20 years ago we expected it, " says Egli, "but I'm still surprised that this promise is becoming a reality.…”

Local drug delivery to the inner ear: Principles, practice, and future challenges

“…A look towards our neighboring specialty – ophthalmology – reveals that regular intraocular injections are accepted by patients for years, thus, intracochlear and intralabyrinthine injections will likely also be accepted by patients if there is an appropriate risk benefit ratio. Transplantation of stem cells have shown partial success in the inner ear in animals (Chen et al 2012) and in the eye in humans (da Cruz et al 2018), and a first human gene therapy trial for severe-to-profound hearing loss is ongoing ( ClinicalTrials.gov Identifier).…”