Human eye tissue afflicted with macular degeneration. (Source: Wikimedia Commons, Andy Nestl) The most potent stem cells are coming to patients after helping blind (and nearly blind) mice see for years.
More than eight clinical trials have launched, or will soon launch, in which retinal cells made from pluri-and-multi-potent stem cells are given to patients with dry age-related macular degeneration (AMD) and/or Stargardt’s macular dystrophy (SMD).
“Exciting both for us and, most importantly, for the patients,” Stem Cells Inc. Executive Vice President Ann Tsukamoto told Drug Discovery & Development
ACT’s ES cell trials
The most visible two trials come from teams led by Advanced Cell Technology (ACT) Chief Scientific Officer Robert Lanza and Jules Stein Eye Institute physician Steven Schwartz. In a recent article in The Lancet, the teams reported that, for the first time, cells made from pluripotent embryonic stem (ES) cells have proven safe in humans for medium- to long-term use— three years— while demonstrating “possible biological activity.” More than half the patients experienced restoration of some sight.
Specifically, retinal pigmented epithelium (RPE) cells made from ES cells were given, in two Phase 1 / 2 trials, to nine patients with SMD, and to nine patients with “dry” AMD. SMD is the leading cause of juvenile blindness; AMD is the leading cause of adult blindness. No effective treatments currently exist for either. All 18 patients had severe vision loss.  In these patients, the light-receiving (photoreceptor) cells of the retina often degenerate to the point of near-complete blindness. 
Patients received one of three boluses (50,000, 100,000 or 150,000) of ES cell-derived retinal cells under the retina with the worse vision. The cells were well-tolerated for up to 37 months. There was no hyper-proliferation or rejection in treated eyes during a median follow-up of 22 months. There were problems associated with vitreo-retinal surgery and immunosuppression, but none associated with the cells.
Subsequent tests showed that 10 of 18 treated eyes experienced “significant” improvements in vision, the report said, with eight patients reading over 15 additional letters in the first year. Visual acuity increased or remained stable in seven patients, although one patient’s ability to read decreased by more than 10 letters. The trial is small, and not randomized, so the possibility of placebo effect is real— as with all Phase 1 clinical trials. However, the fact that untreated eyes did not show similar visual improvement is “promising,” the report concluded.
Robert Lanza, CSO of ACT and senior author of a key new Lancet study on embryonic stem cells in patients with severe eye diseases.Lanza told Drug Discovery & Development: “We hope to start Phase 2 clinical trials by the end of the year. This will involve a much larger number of patients—100 with SMD Stargardt’s, and about 50 with dry AMD.” Lanza and Schwartz are also planning a myopic macular degeneration ES-cell trial.
Shots vs. sheets
Some in the ophthalmology field have criticized the choice of injecting boluses of cells, claiming it is more “natural” to transplant RPE cells in sheets. RPE cells form a supportive layer in the eye that emits growth factors and maintains photoreceptors and rods. RPE cells are severely impacted in AMD.
Lanza said sheets may be needed in “wet” macular degeneration— where blood vessels grow out of control and can dislodge the retina’s macula. But this may not be true of the “dry” form, where yellowish deposits form on the retina.
Regardless, “the sheets are more invasive, and the denuded areas of Bruch’s membrane where they are being used may not have many photoreceptors left to rescue (even if they work),” Lanza said. “However, dissociated cells can easily seed in transition zones to restore the RPE layer.”
Trial of neural stem cells
Meanwhile, Stem Cells Inc. released an interim report in June, detailing the condition of seven advanced dry AMD patients who were treated with fetal neural stem cells (NSCs). After one year, the rate of retinal atrophy in the treated eyes of four patients slowed 65% to 70%. Now, six months out, the slow-down rate in the remaining three patients’ treated eyes is “not inconsistent with this, but we want to have their one-year data before we define amounts,” Tsukamoto told Drug Discovery & Development.
Four patients experienced improved ability to sense the contrast between light and dark, she said. 
Stem Cells Inc.’s NSCs are not naturally found in the eye, but, when implanted, they do some of the work of lost RPEs, Tsukamoto said.
“[Stem Cells Inc.] published two papers detailing the preclinical studies of our cells in retinal degeneration," Tsukamoto said. Those studies confirmed the “clinical potential” of NSCs in the way they preserve photoreceptors, and visual function, compared to controls.
This indicates “at least one mechanism of action involves replacing a function which has been lost due to the diseased RPE. We postulate that both active and protective mechanisms account for the outcomes observed in the animal studies,” said Tsukamoto.
Tsukamoto also said the group’s pre-clinical work shows that human NSCs phagocytose, or eat, photoreceptor outer segments. In doing so, they “preserve the synaptic contacts between the photoreceptor cells and other retinal neurons. The phagocytosis function is one key function performed by healthy RPE that is lost in AMD. The fact that our human neural stem cells perform a similar phagocytic function…provides evidence of this mechanism.”
Fascinatingly, she added, it may be that fetal neural stem cells and RPEs perform a similar phagocytic function because they “develop from the same neuroepithelia cell layer.”
Stem Cells Inc. plans to launch a Phase 2 trial by the start of the year. The company's cells are purified from a single fetal tissue serving as a master batch, then expanded countless times over to fill banks of robust, well-characterized cells that, in two trials so far, have behaved exactly as predicted by pre-clinical work.
Japan’s world-first iPS cell trial
The Riken Institute’s induced pluripotent stem (iPS) cell trial, perhaps the most famous recent AMD trial, has only treated one patient so far. In that trial, Riken ophthalmologist Masayo Takahashi reprogrammed a “wet” AMD patient’s skin cells, producing pluripotent stem cells from them, then differentiating them into RPEs. She did this with CiRA, the institute of the Nobel Prize-winning creator of iPS cells, Shinya Yamanaka. 
A sheet of the cells was transplanted into one of the patient's eyes in mid-September. All is going well, and Takahashi “is planning to work on the second case shortly,” Program Officer for the Japan Science and Technology Agency Chihiro Akazawa told Drug Discovery & Development.  “Her plan was to confirm the safety and efficacy of the treatment with five patients.”
Akazawa added that Japan has been so intensely aware of the global interest in stem cells— and Yamanaka and Takahashi’s work in particular—that the government created new regenerative medicine rules, which are strict enough to preserve safety, yet leave enough leeway to make Japan competitive.
The near future
Two other high-profile groups plan to give pluripotent cell-derived RPEs to AMD patients soon. University College London biologist Peter Coffey, backed by Pfizer and The London Project to Cure Blindness, has helped many a blind rodent see with RPE cells made from ES cells, which were then transplanted on scaffolds. That group has received regulatory approval to launch a trial for wet AMD patients at Moorfield’s Eye Hospital in the UK. (Coffey is now at the University of California Santa Barbara (UCSB).)
And UCSB stem cell researcher Dennis Clegg is awaiting FDA approval for a California Institute of Regenerative Medicine-backed trial also involving RPEs from ES cells. He, too, will transplant the cells via a scaffold. That trial, for dry AMD patients, will be conducted at City of Hope hospital in Los Angeles, California.