The Retina Revolution: Signaling Pathway Therapies, Genetic Therapies, Mitochondrial Therapies, Artificial Intelligence

Edward H. Wood; Edward Korot; Philip P. Storey; Stephanie Muscat; George A. Williams; Kimberly A. Drenser

Disclosures

Curr Opin Ophthalmol. 2020;31(3):207-214. 

In This Article

Mitochondrial Therapies

Mitochondria are double membrane-bound organelles present in all eukaryotic cells critical for energy metabolism. Although each cell has 2000–10 000 mitochondria, each mitochondrion contains 8–10 copies of maternally inherited mitochondrial DNA encoding for 37 genes, including 13 proteins that are subunits of the electron transport chain (ETC), and all of the machinery (22 tRNAs, 16S and 12S ribosomal RNA) required to produce those proteins (Figure 3). The neural retina and retinal pigment epithelium (RPE) are among the most metabolically active tissues in the body and are preferentially affected in mitochondrial disease in part because of the resulting high concentrations of reactive oxygen species (ROS).[47] In addition to the RPE and neural retina being frequently involved in inherited mitochondrial disease,[48] there is a large body of evidence supporting mitochondrial dysfunction as a predominant mechanism of disease in diabetic retinopathy,[49] retinopathy of prematurity,[50] and AMD.[51,52]

Figure 3.

Mitochondrial biology: although most proteins used by the mitochondria are encoded by nuclear DNA and imported into the mitochondria for use, each mitochondrion contains 8–10 copies of its own DNA that primarily generates components of the mitochondrial electron transport chain.

Mitochondrial diseases are currently untreatable, in part because of difficulties in modeling and understanding mitochondrial dysfunction. The mitochondrial network is highly dynamic with mitochondria undergoing biogenesis, fusion, fission, and mitophagy.[53] In addition, mitochondria do not readily import RNA, making mitochondrial gene editing with CRISPR–Cas difficult (but possible with TALENS that utilize amino acids for their guide sequence). Our group and others have shown that mitochondrial diseases typically manifest only when the % of mutated versus WT mitochondrial DNA (mitochondrial heteroplasmy) exceeds a threshold amount[54] (Figure 4), but heteroplasmy is widely variable between patients with the same mutation, between tissue types in the same patient, and even overtime in cell culture from a specific tissue. In spite of this, many compounds have been utilized with variably efficacy to treat mitochondrial dysfunction in retinal cells within in vitro and animal models of disease including rapamycin,[55] metformin,[56] nicotinamide,[57] resveratrol,[58] humanin,[59] coenzyme Q10,[60] zeaxanthin,[61] and others.[62]

Figure 4.

Mitochondrial heteroplasmy: mitochondria, cells, tissues, and organisms vary in the relative percentage of mutated versus wildtype mitochondrial DNA (so-called heteroplasmy). Heteroplasmy has been found in every individual tested, but only causes disease when it exceeds a certain bioenergetic

Tetrapeptide SS-31 (Elamipretide, Stealth BioTherapeutics) is a therapeutic candidate for mitochondrial dysfunction currently undergoing an ongoing Phase 2 trial for AMD patients with noncentral geographic atrophy (NCT03891875). Elamipretide stabilizes cardiolipin in the inner mitochondrial membrane, thereby attenuating the damaging effects of ROS.[63] Another potential therapy is 'photobiomodulation,' which has shown promising results in randomized clinical trials.[64] Our group and others have shown that light (especially red to infrared light [590–850 nm]) can improve mitochondrial function because cytochrome c-oxidase in the ETC absorbs light and subsequently increases mitochondrial respiration and Adenosine Triphosphate production/[65–67]

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