STEM CELL THERAPIES, GENE-BASED THERAPIES, OPTOGENETICS, AND RETINAL PROSTHETICS: Current State and Implications for the Future

Abstract

Purpose: To review and discuss current innovations and future implications of promising biotechnology and biomedical offerings in the field of retina. We focus on therapies that have already emerged as clinical offerings or are poised to do so.

Methods: Literature review and commentary focusing on stem cell therapies, gene-based therapies, optogenetic therapies, and retinal prosthetic devices.

Results: The technologies discussed herein are some of the more recent promising biotechnology and biomedical developments within the field of retina. Retinal prosthetic devices and gene-based therapies both have an FDA-approved product for ophthalmology, and many other offerings (including optogenetics) are in the pipeline. Stem cell therapies offer personalized medicine through novel regenerative mechanisms but entail complex ethical and reimbursement challenges.

Conclusion: Stem cell therapies, gene-based therapies, optogenetics, and retinal prosthetic devices represent a new era of biotechnological and biomedical progress. These bring new ethical, regulatory, care delivery, and reimbursement challenges. By addressing these issues proactively, we may accelerate delivery of care to patients in a safe, efficient, and value-based manner.

Fig. 1.

Stem cell therapy. Pluripotent retinal stem cells are most commonly derived from embryonic stem cells and/or iPSCs and may give rise to any assortment of retinal cell types including retinal pigment epithelial cells, photoreceptors, retinal organoids, and others.

Fig. 2.

Gene therapy. Nonfunctioning cell containing the mutated gene of interest is transduced with a normal-functioning copy of the gene in the form of a plasmid packaged within a viral vector. After viral transduction, the plasmid is read, and the gene product is shuttled to the site of interest (in this case plasma membrane).

Fig. 3.

Gene therapy with sub-cellular targeting. Gene products may also be shuttled to sub-cellular compartments for specific organelle modulation.

Fig. 4.

Gene editing approach. It is possible to use a variety of molecular scissors to induce specific dsDNA breaks at sites of DNA mutations. After the break occurs, the nucleic acid sequence is either repaired randomly by “non-homologous end-joining” (NHEJ), or specifically by “homology-directed repair” (HDR).

Fig. 5.

Gene editing with clustered regularly interspaced short palindromic repeats (CRISPR). CRISPRs interface with CRISPR-associated systems (Cas) that act as molecular scissors to cleave-targeted DNA segments with very high specificity. The most commonly used CRISPR-Cas9 system uses a guide RNA. A component in the target DNA (protospacer adjacent motif [PAM]) is required for Cas9 to recognize and cleave at the target location.

Fig. 6.

Opsin classification. Type 1 opsins are microbial transmembrane proteins that serve as either channels or pumps to facilitate ion flow across membranes in response to light, whereas Type 2 opsins are transmembrane G-protein–coupled receptors that facilitate intracellular signaling in response to light (such as human rhodopsin).

Fig. 7.

Opsin and neuronal subpopulation of choice. This figure depicts three main retinal cell types targeted for optogenetics (RGCs, bipolar cells, and photoreceptors) along with representative opsins most commonly targeted to these distinct cellular layers.

Fig. 8.

Retinal prosthetic implant placement. A. Cross-sectional depiction of a healthy retina. B. Cross-sectional depiction of a degenerate retina lacking photoreceptors. Epiretinal implants are placed on top of the nerve fiber layer, whereas subretinal implants replace missing photoreceptors in a degenerate retina and hence are in direct contact with the inner nuclear layer. Suprachoroidal implants are placed between the choroid and the sclera.