Macular degeneration patients regain sight with stem cell implants

Two patients with macular degeneration regained reading vision after receiving stem cells implanted with a new technique, according to researchers.

Professor Lyndon da Cruz from Moorfields Eye Hospital NHS Foundation Trust and his colleagues engineered a patch of retinal pigment epithelium cells from human embryonic stem cells to treat the patients, both of whom had suffered sudden severe sight loss from wet age-related macular degeneration (AMD).

The technique might also be used to treat the dry form of the disease, Professor da Cruz and his colleagues wrote in a report on the Phase I trial in Nature Biotech.

“The results suggest that this new therapeutic approach is safe and provides good visual outcomes," Professor da Cruz said. “The patients who received the treatment had very severe AMD, and their improved vision will go some way towards enhancing their quality of life.”

AMD damages the retinal pigment epithelium (RPE), a layer of cells that separates blood vessels from the nerve layer and nourishes the retina.

Human embryonic stem cells hold promise as a source for replacing damaged or missing cells because of their availability, pluripotency and unlimited capacity for self-renewal. But they come with the risk of neoplastic change, uncontrolled proliferation and differentiation to inappropriate cell types.

Suspensions of retinal pigment epithelium cells derived from human embryonic stem cells have been transplanted in human subjects with dry AMD and Stargardt’s disease, but the extent of cell survival and restoration of vision remains unclear, the researchers wrote.

A recent, single-patient report described transplantation of a retinal pigment epithelium patch derived from autologous induced pluripotent stem cells on its own secreted basement membrane. The patch survived with maintenance, but no improvement, of visual acuity at 12 months.

Stem cell patch

Professor Da Cruz et al. created a patch from a biocompatible monolayer of embryonic stem cells on a synthetic membrane coated with human vitronectin.

In contrast to retinal pigment epithelium suspensions, the cells on the patch were delivered fully differentiated and polarised, with a tight junction barrier, a form the researchers termed “close to their native configuration”.

The synthetic membrane allowed the surgeons to handle the patch relatively easily, and their specially designed tool protected the patch within its tip, reducing the risk of cell loss, cell distribution within the eye, and physical damage to the retinal pigment epithelium monolayer.

After experiments in mice and pigs, the researchers placed one patch each in the subretinal spaces, under the foveas, in the affected eyes of two patients. They stabilised the patches with immunosuppression consisting of perioperative oral prednisolone and long-term intraocular fluocinolone implants.

In both patients, the researchers could see human embryonic stem cell retinal pigment epithelium over the full area of the patch 12 months later. They could also see darker patches showing uneven autofluorescence, suggesting that retinal pigment epithelium cells might be migrating off the patch onto adjacent areas deficient in this type of cell. They could not find any sign of neoplastic transformations.

Improvements

Best corrected visual acuity improved over 12 months from 10 to 39 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one patient and from 8 to 29 letters in the other.

Reading speed on the University of Minnesota MNRead test improved from 1.7 to 82.8 in one patient and from 0 to 47.8 words/min in the other.

“In the months before the operation, my sight was really poor and I couldn’t see anything out of my right eye,” said one of the patients, Douglas Water, 86, from London, according to the press release. He received the treatment 3 months after developing severe wet AMD in July 2015.

“After the surgery, my eyesight improved to the point where I can now read the newspaper and help my wife out with the gardening. It’s brilliant what the team have done and I feel so lucky to have been given my sight back.”

Using microperimetry, the researchers tested for perception of microlocalised light stimuli, and found visual fixation at the centre of the patch and vision over the patch in both patients.

On full-field electro-retinography at 6 months in the operated eyes, the researchers found mild but consistent reduction in photoreceptor function and consequent electro-ocolugraphy reduction at 6 months in both patients. At 12 months, photoreceptor function recovered in one of the patients.

Ocular pressures never went up in either patient, and the researchers did not find any changes of concern in liver or renal function. In one patient, the fluocinolone implant suture was exposed, requiring revision surgery.

In the other patient, diabetes worsened following oral prednisolone, and was treated medically. In addition, this patient’s retina detached and required peeling of the proliferative vitreoretinopathy membranes, inferior retinectomy of the peripheral retina and laser to the retinectomy edge.

Compared with stem cell suspensions, the main disadvantage of the patch is that it requires a purpose-built delivery tool and a more complicated surgery, the researchers wrote. And the use of hESCs may require immunosuppression, unlike an autologous cell source. 

“This study represents real progress in regenerative medicine and opens the door to new treatment options for people with age-related macular degeneration,” said co-investigator Professor Pete Coffey, from the UCL Institute of Ophthalmology.