RETINAL DEGENERATIVE DISEASE

Stem cell-based therapy provides a promising approach that may one day help to restore and sustain retinal function for patients with retinal degenerative diseases, according to Ting Xie PhD. “It is still early days and a lot of obstacles remain to be overcome but much progress has been made in the field of stem cell research in recent years and we are moving closer to our ultimate goal of being able to generate patient-specific retinal pigment epithelial (RPE) cells, photoreceptor cells and retinal ganglion cells for treating retinal degenerative diseases,†Dr Xie told delegates attending the World Ophthalmology Congress.

Dr Xie, investigator at the Stowers Institute for Medical Research in Kansas City and professor at the Department of Anatomy and Cell Biology at the University of Kansas School of Medicine, US, noted that retinal degeneration is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy and glaucoma.

In a broad overview of progress made to date, Dr Xie said that researchers have demonstrated that stem-cell transplants can survive, migrate, differentiate and integrate within the retina. Different types of stem cells can be applied to treat retinal degenerative disease including human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), Muller cells and induced neural progenitor cells (iNPCs).

Breakthroughs

Major advances have been made in recent years in the generation of hESC-derived retinal pigment epithelium, said Dr Xie. He cited key breakthroughs such as the differentiation of primate embryonic stem cells into functional RPE cells by the Takahashi group in 2004, the differentiation of hESCs into RPE cells by the Coffey group at the University of London in 2008, and the generation of functional RPEs from hESCs by both the Lund group in Oregon and the Reubinoff group in Hadassah-Hebrew University in 2009.

In 2011, Advanced Cell Technology (ACT) was given FDA approval to treat dry AMD using hESC-derived RPE cells. Earlier this year, Schwartz et al at the University of California and scientists in ACT announced the clinical trial preliminary report on AMD which showed that the hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation or apparent rejection after four months. Using stem cells for the generation of photoreceptors has also proved a fruitful line of research, said Dr Xie.

In 2005, Hara et al at Nara Medical University in Japan generated photoreceptors from mouse ESCs in co-culture with chicken retina. A year later, Kirk et al at the University of Missouri-Columbia produced mouse ESCderived retinal progenitor cells, followed by Reubinoff et al at Hadassah-Hebrew University and Reh et al at the University of Washington who produced human ESCderived retinal progenitors.

In 2009, the Reh group also showed that hESC-derived photoreceptors restored the function of the cone-rod homeobox (crx)-deficient eye. In another important study, Lamba et al in 2009 showed that after transplantation of hESC cells into the subretinal space of adult Crx deficient mice, the hESC-derived retinal cells differentiated into functional photoreceptors and restored light responses to the animals.

Turning to patient-specific pluripotent stem cells (iPSCs), Dr Xie said that researchers have shown the ability of iPSCs to generate RPE cells that are functional in vivo. Earlier this year, Lako et al at Newcastle University developed an efficient strategy to differentiate human ESCs and iPSCs into photoreceptor cells. “The advantage of this approach is that the generation of patient-specific retinal cells for transplantation may minimise potential immune rejection,†said Dr Xie.

In terms of the potential of using retinal progenitor cells (RPCs) and Muller cells to treat retinal degenerative disease, Dr Xie said that Cepko et al. at Harvard University have shown in 2000 that Muller cells in mice can proliferate following injury. In 2007, the Khaw and Limb groups at the Institute of Ophthalmology in London showed that human Muller cells exhibit neural stem cell characteristics differentiating into retinal lineages, while the following year Reh et al showed that Muller cells can regenerate retinal neurons, but not photoreceptors, in mice.