New possibilities

Susanne Binder MD 

Stem cell therapy is opening up exciting new therapeutic possibilities in degenerative eye diseases such as advanced age-related macular degeneration (AMD), Susanne Binder MD told delegates attending the 2015 Congress of the European Society of Ophthalmology (SOE) in Vienna, Austria.

“Today we have increasing solutions for better cell sources, their adhesion and basal lamina construction. However, progress for successful human retinal transplantation is constant but comes only in small steps. We still need better timing of intervention and case selection in order to demonstrate that transplanted cells are well tolerated, in which case we may be able to use them much earlier in the course of the disease,” she said.

The rationale for using cell transplantation in AMD, a disease with dysfunctional retinal pigment epithelium (RPE), is well founded, explained Dr Binder.

“Human retinal transplantation followed a lot of experimental research showing that transplanted RPE cells have the potential to rescue photoreceptors. RPE is incapable of self-renewal and is considered to be the initial site for events leading to AMD. Furthermore, it is easily accessible as a visible pigmented monolayer,” she said.

The molecular mechanisms for non-neovascular AMD are not fully defined, with several distinct pathways probably leading to oxidative stress culminating in RPE dysfunction and death, said Dr Binder.

TREATMENT STRATEGY

Dr Binder identified three major types of treatment strategy: firstly, preventing RPE dysfunction or death, which would necessitate early intervention; secondly, providing support to stressed RPE to maintain its function for an extended period; and thirdly, replacing diseased RPE with a new healthy RPE layer.

In the early 1990s many experiments focused on RPE replacement and it was shown that extrafoveal RPE can provide foveal function with retinal translocation. Foetal and adult RPE were tested as potential cell sources, but these cells degenerated easily upon implantation and the sources were limited, said Dr Binder.

Further research using delivery methods such as sheets and suspensions of RPE and photoreceptors brought mixed results, said Dr Binder.

“Overall we found out the hard way that sources of autologous transplants are quite limited and that multiple complications may result from surgery of sheets using RPE. We also discovered that autologous cells from the periphery share the same genetic defect if they are being moved to the centre,” she said.

PHOTORECEPTOR REGENERATION

Despite these problems, some patients did show visual acuity improvement with evidence of photoreceptor regeneration. The challenge now was to refine the techniques and find a more abundant cell source to create a feasible treatment, said Dr Binder.

“It was always my conviction that retinal transplantation should be a procedure which is atraumatic, easy to perform and with minimal risk of complications," she said.

Potential new sources for robust RPE cells include several distinct stem cell categories: omnipotent, embryonic, pluripotent, multipotent, mesenchymal and adult stem cells. In ophthalmology, embryonic stem cells and induced pluripotent stem cells (iPSCs) are the two groups most used in clinical studies and seem to offer the most promise, said Dr Binder.

“Many technical and regulatory breakthroughs have made stem cell therapies for AMD more plausible. We can now derive RPE cells from embryonic stem cells, we have seen advances in the use of iPSCs to replace photoreceptor loss, and conducted clinical trials using stem cell derived RPE in retinal degenerative disease showing short-term safety,” she said.

Embryonic stem cells offer several advantages, said Dr Binder: large scale expansion is possible, they are pathogen free, well characterised and have a high degree of similarity to in situ RPE by genetic testing. They are also reproducible, with no embryo destruction, and stem cell plasticity can optimise their ability to attach on aged or diseased Bruch’s membrane and reduce rejection. Their main disadvantages include the ethical consideration of using human embryonic stem cells and the fact that long-term immunosuppression will probably be required.

Induced pluripotent stem cells, by contrast, carry no risk of immune rejection, said Dr Binder.

“For AMD, human iPSCs have been differentiated into RPE and it has been shown that they have the full range of morphologic and functional properties characteristic of RPE cells in vitro and in vivo. The disadvantage is that affected patients are old and probably carry the same genetic abnormalities,” she said.

Other interesting lines of research include stem-cell derived photoreceptor cells, which have shown early promise in RPE rescue in animal models, and also a technique using genetic non-viral in vitro RPE modification-plasmids to overexpress pigment-epithelium-derived factor (PEDF).

PEDF is thought to be not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularisation, said Dr Binder. A multicentre trial in eight European centres has recently commenced to assess the viability of replacing degenerated RPE cells with genetically modified PEDF-producing cells.

Susanne Binder:
susanne.binder@wienkav.at