Japanese scientists have described an experimental treatment using induced pluripotent stem cells (iPSCs) effective at halting age-related macular degeneration (AMD), with no serious side effects noted after 2 years of follow-up.
"This represents a landmark," says George Q. Daley, MD, PhD, Dean of Harvard Medical School and a leading stem cell researcher. "It's the first time any patient has been treated with cellular derivatives of iPS cells. So it's definitely a world first."
In this study, Masayo Takahashi, MD, PhD, and colleagues from the RIKEN Center for Developmental Biology describe the treatment of late-stage wet AMD in a 77-year old woman who received a unilateral transplantation of a sheet of RPE cells derived from autologous iPSCs.
The patient was diagnosed with bilateral polypoidal choroidal vasculopathy in 2010. Despite ensuing treatment with 13 injections of ranibizumab and aflibercept over a period of 29 months, the vision in her right eye continued to decline from 20/130 to 20/200.
The team generated iPSCs from the patient’s own skin fibroblasts and cultured them into a RPE cell monolayer sheet. Prior to use, the iPSC-RPE line was subjected to extensive quality and safety characterization, including whole-genome sequencing and expression analyses to ensure both genetic integrity and expression profiles consistent with native RPE tissue.
And then, in September 2014, surgeons removed the neovascular membrane from her right eye and transplanted an autologous iPSC-derived RPE cell sheet that measured 1.3×3.0 mm under the fovea. The patient demonstrated a transient elevation in IOP to 28 mm Hg in the early postoperative period (5 to 8 weeks), but was successfully managed with temporary administration of anti-glaucoma eyedrops.
Her vision did not experience any further deterioration, and stabilized at 20/200. Her scores on the National Eye Institute Visual Functioning Questionnaire (VFQ-25) indicated an improved visual function and general health, increasing from 48.8 to 58.3.
Throughout 1 year of follow-up, no serious complications, unexpected proliferation or signs of local or systemic malignant disease were observed. There were also no indications of graft rejection up to the most recent visit in December 2016.
The results are “a proof of principle that iPS cell-based therapy is feasible,” says Kapil Bharti, PhD, a molecular cell biologist at the National Eye Institute who is also developing iPSCs for treating AMD.
Although the 2-year results are promising, a longer follow-up will be necessary to ensure no additional adverse events occur over time.
This carefully designed study stands in stark contrast to the treatment of 3 elderly women who were blinded by bilateral intravitreal injections of autologous adipose tissue-derived cells. Reports of both were published in the March 16 issue of the New England Journal of Medicine.
Dr. Daley, who wrote an editorial accompanying the 2 papers, said that the differences in the conduct of the Japanese team and of those responsible for blinding the 3 women was “striking.” He noted that the Japanese scientists followed proper protocol by treating only 1 eye, ensuring vision would be maintained in the other if something went wrong.
The team exercised further caution when they decided not to treat their second enrolled patient, despite the encouraging results from the first. Their reservations stemmed from the second patient’s moderate response to anti-VEGF therapy and the team’s concerns over the tumorigenicity of copy-number mutations found in his iPSC-RPE line.
Once the team gains more experience with the technique, they plan to extend it to patients with earlier-stage AMD in an effort to preserve vision.