This article was reviewed by Russell N. Van Gelder, MD, PhD
Neuronal cell replacement therapies remain a challenge in retinal diseases. Some fish and salamanders have the innate ability to regenerate retinal tissue after injuries and, as Russell N. Van Gelder, MD, PhD, pointed out, if researchers could harness this ability in humans, the possibilities would be great for repairing or replacing damaged tissue in a wide variety of retinal diseases. Stem cells are the key to cell replacement therapies.
Stem cells are cells that have not terminally differentiated and still have the potential to become many types of terminal cells, said Van Gelder, from the Department of Ophthalmology at the University of Washington in Seattle. We all started as embryonic stem cells in the earliest phases of development.
Related: Retinal pathologies challenging to image with current technologies
Van Gelder went on to explain that there are now methods to create equivalently totipotent stem cells from individual induced progenitor stem cells derived from an individuals blood or epithelial cells.
The overarching goal is to create a cell type that needs replacement from a stem cell precursor, he said.
A major achievement in this quest for regenerative ability occurred in 2014 when an entire eye cup was grown from progenitor stem cells.
Van Gelder also described a study1 in which green fluorescent proteinlabeled retinal precursors derived from embryonic stem cells were transplanted into the subretinal space of macaques. Three months after the procedure, the researchers demonstrated that the bolus of cells persisted and had outgrowth of axons that were seen going to the optic nerve and on to the brain.
This result establishes the validity of a stem cell-based approach for doing regenerative medicine in primates, he said.
Related: Persistent retinal detachment associated with retinoblastoma
Replacement therapy hurdles As of now, however, no stem cell-based replacement treatment has received FDA approval. The problems preventing establishment of a treatment have been technical in nature and include correct cellular differentiation as well as generating adequate numbers of cells for large transplantation experiments, establishing correct cell polarity and connectivity, and ensuring the safety of these approaches regarding tumor or hamartoma formation, Van Gelder explained.
Managing inflammatory responses is a problem after cell transplantation. He cited a Japanese study2 of individual progenitor cell-derived retinal progenitor cells transplanted subretinally in monkey models.
Even with an immune HLA-matched donor, there was still a marked inflammatory response at the site of the transplantation, Van Gelder said. This and other inflammatory responses will have to be managed for cell transplantation to be successful. Related: Intravitreally injected hRPCs improve vision in retinitis pigmentosa cases
There are regulatory hurdles to clear. The FDA Center for Biologics Evaluation and Research regulates cellular therapy products, human gene therapy products, and certain devices related to cell and gene therapy.
Van Gelder recalled the well-publicized case of transplantation of fat-derived mesenchymal cells into patients eyes, resulting in loss of vision bilaterally. He pointed out that it is important to temper patient expectations regarding these therapies and to ensure that the work is being done with the highest degree of ethical integrity.
While great progress has been made in this field, significant barriers remain to the successful adoption in the clinical setting in the coming years, Van Gelder concluded. The barriers to cell replacement should be overcome.
Read more by Lynda Charters
Russell N. Van Gelder, MD, PhD e: firstname.lastname@example.org Van Gelder has no financial interests in this subject matter. He serves on the advisory committee for the National Eye Institute Audacious Goals Initiative.
1. Chao JR, Lamba DA, Kiesert TR, et al. Transl Vis Sci Technol. 2017;6:4; doi:10.1167/tvst/6/3/4
2. Fujii S, Sugita S, Futatsugi Y, et al. A strategy for personalized treatment of iPS-retinal immune rejections assessed in cynomolgus monkey models. Int J Mol Sci. 2020;21(9):3077. doi:10.3390/ijms21093077
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