Stem Cell Treatment for Glaucoma

Novel regenerative approach uses iPSC-derived trabecular meshwork-like cells. Cheryl Guttman Krader reports

Astem cell-based approach for restoring trabecular meshwork (TM) function and IOP control in eyes with primary open-angle glaucoma (POAG) appears promising in preclinical studies.

“The number of cells residing within the TM declines with age, and it is particularly low in eyes with POAG. The concept that it might be possible to restore IOP control in glaucomatous eyes by restoring TM cellularity has been around for some time, and with the development of induced pluripotent stem cells (iPSCs), the possibility emerged that we might be able to do that using autologous material,” said Markus H Kuehn PhD.

Dr Kuehn’s group used human skin samples to create iPSCs that could be differentiated into a cell type resembling primary TM cells. The group investigated the effects of injecting the iPSCderived TM-like cells (“iPSC-TMs”) in two genetically engineered mouse models of glaucoma chosen because they exhibit loss of TM cells without gross alteration of TM structure.

The studies included wild-type animals as one control arm and groups of transgenic mice receiving anterior chamber injections of labelled iPSC-TMs or phosphate-buffered saline (PBS). The study results showed that iPSC-TM transplantation was associated with a rapid increase in TM cell density and prevented the reduction in aqueous humour outflow facility and increase in IOP observed in the PBS-treated transgenic control group.

Surprisingly, the injected labelled iPSC-TMs represented only a small fraction of the increased TM cellularity, Dr Kuehn said.

“Gene expression analysis of the TM post-transplantation indicated the increase was secondary to cell proliferation,” he said.

Advancing into experiments performed in perfusioncultured human eyes, the researchers similarly found that the injected iPSC-TMs integrated into the TM and resulted in increased TM cellularity mainly accounted for by inducing proliferation of endogenous cells.

“The fact we are inducing division of endogenous cells has advantages and disadvantages. One advantage is that, as opposed to exogenous material, the endogenous cells do not trigger an inflammatory reaction, so host immune rejection may not present a significant problem for this approach. In addition, it suggests that long-term survival of transplanted material may not be necessary, and that in turn suggests the possibility of creating an iPSC line that could be used for all donors and avoiding the need for a patient-specific iPSC line,” Dr Kuehn said.

Moving ahead, there are challenges and questions to address. From a technical perspective, the researchers hope to increase the efficiency and targeting specificity of the delivered iPSC-TM cells.

Noting the human eye experiments were done using eyes from older adults without frank glaucoma, Dr Kuehn said it remains to be seen whether TM cells in eyes with POAG are irreversibly damaged or modified in ways that prevent rescue and if the approach can work in secondary types of glaucoma. Further research is also needed to determine how long the functional rescue benefit persists after iPSC-TM injection.

Dr Kuehn presented these findings at ARVO 2022 in Denver, Colorado, US.

Markus H Kuehn PhD is a professor of ophthalmology and visual sciences in the Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, US. markus-kuehn@uiowa.edu

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