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Glaucoma Opinion IGR 11-3

Advances in stem cell therapy for glaucoma

Keith Martin

The eye is an attractive target for stem cell approaches as endogenous repair is limited and functional damage is often permanent
Stem cells are multipotent cells with the capacity to self-renew and to produce daughter cells capable of differentiating into multiple mature cell types. The potential use of stem cell therapy to treat degenerative eye diseases such as glaucoma is receiving much current attention. The eye is an attractive target for stem cell approaches as endogenous repair is limited and functional damage is often permanent. Multiple approaches to stem cell therapy are conceivable, but if any of these are to be translated to the clinic further significant advances will be required.

Potential treatment strategies

Theoretically, the most direct stem cell based treatment for glaucoma would involve stimulation of endogenous retinal repair mechanisms. In fish and amphibians, retinal regeneration is an automatic process that proceeds via differentiation of ocular stem cells located in the ciliary marginal zone. In adult mammals, however, retinal regeneration after injury or in neurodegenerative disease does not occur. While mammalian retinal progenitor cells have been identified in vitro, they appear to remain quiescent in vivo. Within the adult mammalian CNS, neurogenesis is limited to discrete regions such as the hippocampus and elsewhere the environment is notoriously resistant to the generation and integration of new neurons. Techniques to enhance neuronal repair in the adult human eye remain at an early stage of development.

Alternatively, degenerated retinal neurons could be replaced by transplanting suitable precursor cells. It has been demonstrated that neural precursor cells derived from embryonic stem cells, when transplanted into the eye, can migrate into the retina and express markers of mature retinal neurons.1 In addition, retinal progenitor cells derived from neonatal animals have been shown to achieve retinal integration, to exhibit photoreceptor differentiation and to provide some functional benefit to animals with retinal dystrophy.2 Transplanted foetal-derived hippocampal progenitors also demonstrate the ability to localize to the retinal ganglion cell layer, from where they may extend neurites into the inner plexiform layer and towards the optic nerve head.3 Human adult retina derived Muller stem cells can survive in the glaucomatous rat eye and a small proportion show signs of integration when the inhibitory host retinal extracellular matrix is modulated with chondroitinase.4 However, the migration and incorporation of transplanted cells is difficult to achieve in the adult mammalian retina. Furthermore, the challenge of glaucomatous retinal regeneration does not end at the optic disc. In order to achieve complete functional repair in glaucoma, transplanted cells would not only need to integrate into the existing retinal circuitry but re-establish functional connections with target neurons in the brain with precise regeneration of the retinotopic map. New axons would also require myelination to allow signal conduction at the appropriate velocity. Obviously, significant progress must be made before stem cell therapy can be used to repair the visual pathway so comprehensively. However, it is possible that the survival and partial integration of transplanted cells within the retina could provide alternative benefits by enhancing the survival and function of host RGCs. Recent research suggests that transplantation of stem cells within the CNS can provide neuroprotection to surviving neurons near the graft site.5 Transplanted cells have also demonstrated an ability to modulate immune cell behaviour to reduce tissue damage.6 We have demonstrated that transplantation of oligodendrocyte precursor cells can protect host retinal ganglion cells in a rat model of glaucoma.7

The challenge of glaucomatous retinal regeneration does not end at the optic disc
Alternatively, neurite sprouting by engrafted cells could form local connections within the inner retina that theoretically might increase the receptive field of surviving cells with a concomitant improvement in vision. The hope is that even a small functional benefit in patients with severe visual loss could translate into a meaningful improvement in quality of life. Whether this hope is realistic remains to be seen.

Barriers to progress

Given allogeneic transplantation would likely necessitate longterm immune suppression to avoid graft rejection it would be highly desirable to develop autologous stem cell therapies
There are a number of possible obstacles to the development of a successful stem cell-based therapy for glaucoma. Given allogeneic transplantation would likely necessitate long-term immune suppression to avoid graft rejection it would be highly desirable to develop autologous stem cell therapies. In addition, techniques to promote RGC axon extension, connection and myelination may need to be developed to achieve significant visual field restoration. Finally, the issue of continued disease progression will need to be addressed in order to protect new and host neurons. As with many new approaches in medicine, there is the danger that advocates of stem cell research may promise more than can conceivably be delivered in a realistic timeframe, leading to disappointment, disillusionment and a loss of confidence in the potential of the approach. We must acknowledge that the technology and understanding needed to achieve functional improvement in glaucoma using stem cell therapy is in its infancy.

However, in the absence of any other treatment with the potential to restore vision in glaucoma, further research on the therapeutic use of stem cells in glaucoma remains both justifiable and eagerly awaited.

References

  1.  Banin E, Obolensky A, Idelson M, et al. Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 2006; 24: 246-257.
  2.  MacLaren RE, Pearson RA, MacNeil A, et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006; 444: 203-207.
  3.  Young MJ, Ray J, Whiteley SJ, Klassen H, Gage FH. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. Mol Cell Neurosci 2000; 16: 197-205.
  4.  Bull ND, Limb GA, Martin KR. Human Muller stem cell (MIO-M1) trans plantation in a rat model of glaucoma: survival, differentiation, and integration. Invest Ophthalmol Vis Sci 2008; 49: 3449-3456.
  5.  Meyer JS, Katz ML, Maruniak JA, Kirk MD. Embryonic stem cell-derived neural progenitors incorporate into degenerating retina and enhance survival of host photoreceptors. Stem Cells 2006; 24: 274-283.
  6.  Pluchino S, Zanotti L, Rossi B, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005; 436: 266-271.
  7.  Bull ND, Irvine KA, Franklin RJ, Martin KR. Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma. Invest Ophthalmol Vis Sci 2009; 50: 4244-4253.

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