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Optogenetics for retinal disorders.

Henriksen BS, Marc RE, Bernstein PS - J Ophthalmic Vis Res (2014 Jul-Sep)

Bottom Line: Viral delivery, primarily adeno-associated virus, using intravitreal injection for inner retinal cells and subretinal injection for outer retinal cells, has proven successful in many models.However, targeting optogenetic therapy may present an even greater challenge.Neural and glial remodeling seen in advanced stages of RP result in reorganization of remaining neural retina, and optogenetic therapy may not yield functional results.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.

ABSTRACT
Optogenetics is the use of genetic methods combined with optical technology to achieve gain or loss of function within neuronal circuits. The field of optogenetics has been rapidly expanding in efforts to restore visual function to blinding diseases such as retinitis pigmentosa (RP). Most work in the field includes a group of light-sensitive retinaldehyde-binding proteins known as opsins. Opsins couple photon absorption to molecular signaling chains that control cellular ion currents. Targeting of opsin genes to surviving retinal cells is fundamental to the success of optogenetic therapy. Viral delivery, primarily adeno-associated virus, using intravitreal injection for inner retinal cells and subretinal injection for outer retinal cells, has proven successful in many models. Challenges in bioengineering remain for optogenetics including relative insensitivity of opsins to physiologic light levels of stimulation and difficulty with viral delivery in primate models. However, targeting optogenetic therapy may present an even greater challenge. Neural and glial remodeling seen in advanced stages of RP result in reorganization of remaining neural retina, and optogenetic therapy may not yield functional results. Remodeling also poses a challenge to the selection of cellular targets, with bipolar, amacrine and ganglion cells all playing distinct physiologic roles, and affected by remodeling differently. Although optogenetics has drawn closer to clinical utility, advances in opsin engineering, therapeutic targeting and ultimately in molecular inhibition of remodeling will play critical roles in the continued clinical advancement of optogenetic therapy.

No MeSH data available.


Related in: MedlinePlus

Remodeling severely scrambles networks so that successful ChR2 expression may yield unexpected or fictive responses from surviving retinal cells.
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Figure 6: Remodeling severely scrambles networks so that successful ChR2 expression may yield unexpected or fictive responses from surviving retinal cells.

Mentions: Finally, identifying proper cellular targets has also been challenging. Should light sensing genes be inserted into bipolar cells, amacrine cells, or ganglion cells, and if so, which ones? Figure 4 illustrates the global organization of a normal mammalian retina. The flow of signals in the retina can be thought of as a four-layer model with rods, SWS1-cones (blue cones) and LWS cones (red or green cones) as layer 1; bipolar cells as layer 2; amacrine cell networks that aggregate and tune bipolar cell signals as layer 3; and ganglion cells that collect the amacrine cell and bipolar cell signals as layer 4. Finally, Type AII amacrine cells are unique to mammals and form a hub that aggregates and distributes signals for all types of ganglion cells except primate midget pathways. We refer to this AII amacrine cell hub function as mimicking layer “2.5” as it is interspersed between bipolar cells (BCs) and all other neurons. In RP [Figure 5] the photoreceptor layer 1 is ablated. Assuming that all networks in the neural retina remain normal (which is not true), picking a target network is difficult. If we choose to target ON bipolar cells [Figure 5a] through mGluR6 promoter or enhancer sequences, we must successfully target multiple varieties of ON cells because they have the best chance of appropriately driving retinal ganglion cells. The same is true of the AII amacrine cell, except it would be simpler to target if we knew the right promoter, which we do not. Targeting bipolar cells may be difficult in late-stage because they remodel rapidly and die slowly in most retinal degenerations. While ganglion cells survive the longest, along with some gamma-aminobutyric-acid-ergic (GABA-ergic) amacrine cells,[4849] they require networks to generate appropriate visual signals and drive central pathways with appropriate timing. Thus, the expression of the same opsin in every ganglion cell may create a corrupted visual experience [Figure 5b] even if it restores crude light sensibility. If we can discover transcriptional controls for human foveal midget ganglion cells, it may be possible to target them specifically. Finally, the reality of remodeling is that many target neurons may die, and the remaining networks will become scrambled in ways that may render functional vision via optogenetics unlikely [Figure 6]. It appears that late-stage remodeling is not slowed by interventions such as subretinal transplantation of normal fetal retina into transgenic rats early in life with advanced retinal degenerations.[54] Thus, it is unlikely that even optogenetics signaling will attenuate remodeling, since processes like pathologic de novo neuritogenesis in retinal degenerations depend on retinoic acid signaling rather than network activity.[55]


Optogenetics for retinal disorders.

Henriksen BS, Marc RE, Bernstein PS - J Ophthalmic Vis Res (2014 Jul-Sep)

Remodeling severely scrambles networks so that successful ChR2 expression may yield unexpected or fictive responses from surviving retinal cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307663&req=5

Figure 6: Remodeling severely scrambles networks so that successful ChR2 expression may yield unexpected or fictive responses from surviving retinal cells.
Mentions: Finally, identifying proper cellular targets has also been challenging. Should light sensing genes be inserted into bipolar cells, amacrine cells, or ganglion cells, and if so, which ones? Figure 4 illustrates the global organization of a normal mammalian retina. The flow of signals in the retina can be thought of as a four-layer model with rods, SWS1-cones (blue cones) and LWS cones (red or green cones) as layer 1; bipolar cells as layer 2; amacrine cell networks that aggregate and tune bipolar cell signals as layer 3; and ganglion cells that collect the amacrine cell and bipolar cell signals as layer 4. Finally, Type AII amacrine cells are unique to mammals and form a hub that aggregates and distributes signals for all types of ganglion cells except primate midget pathways. We refer to this AII amacrine cell hub function as mimicking layer “2.5” as it is interspersed between bipolar cells (BCs) and all other neurons. In RP [Figure 5] the photoreceptor layer 1 is ablated. Assuming that all networks in the neural retina remain normal (which is not true), picking a target network is difficult. If we choose to target ON bipolar cells [Figure 5a] through mGluR6 promoter or enhancer sequences, we must successfully target multiple varieties of ON cells because they have the best chance of appropriately driving retinal ganglion cells. The same is true of the AII amacrine cell, except it would be simpler to target if we knew the right promoter, which we do not. Targeting bipolar cells may be difficult in late-stage because they remodel rapidly and die slowly in most retinal degenerations. While ganglion cells survive the longest, along with some gamma-aminobutyric-acid-ergic (GABA-ergic) amacrine cells,[4849] they require networks to generate appropriate visual signals and drive central pathways with appropriate timing. Thus, the expression of the same opsin in every ganglion cell may create a corrupted visual experience [Figure 5b] even if it restores crude light sensibility. If we can discover transcriptional controls for human foveal midget ganglion cells, it may be possible to target them specifically. Finally, the reality of remodeling is that many target neurons may die, and the remaining networks will become scrambled in ways that may render functional vision via optogenetics unlikely [Figure 6]. It appears that late-stage remodeling is not slowed by interventions such as subretinal transplantation of normal fetal retina into transgenic rats early in life with advanced retinal degenerations.[54] Thus, it is unlikely that even optogenetics signaling will attenuate remodeling, since processes like pathologic de novo neuritogenesis in retinal degenerations depend on retinoic acid signaling rather than network activity.[55]

Bottom Line: Viral delivery, primarily adeno-associated virus, using intravitreal injection for inner retinal cells and subretinal injection for outer retinal cells, has proven successful in many models.However, targeting optogenetic therapy may present an even greater challenge.Neural and glial remodeling seen in advanced stages of RP result in reorganization of remaining neural retina, and optogenetic therapy may not yield functional results.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.

ABSTRACT
Optogenetics is the use of genetic methods combined with optical technology to achieve gain or loss of function within neuronal circuits. The field of optogenetics has been rapidly expanding in efforts to restore visual function to blinding diseases such as retinitis pigmentosa (RP). Most work in the field includes a group of light-sensitive retinaldehyde-binding proteins known as opsins. Opsins couple photon absorption to molecular signaling chains that control cellular ion currents. Targeting of opsin genes to surviving retinal cells is fundamental to the success of optogenetic therapy. Viral delivery, primarily adeno-associated virus, using intravitreal injection for inner retinal cells and subretinal injection for outer retinal cells, has proven successful in many models. Challenges in bioengineering remain for optogenetics including relative insensitivity of opsins to physiologic light levels of stimulation and difficulty with viral delivery in primate models. However, targeting optogenetic therapy may present an even greater challenge. Neural and glial remodeling seen in advanced stages of RP result in reorganization of remaining neural retina, and optogenetic therapy may not yield functional results. Remodeling also poses a challenge to the selection of cellular targets, with bipolar, amacrine and ganglion cells all playing distinct physiologic roles, and affected by remodeling differently. Although optogenetics has drawn closer to clinical utility, advances in opsin engineering, therapeutic targeting and ultimately in molecular inhibition of remodeling will play critical roles in the continued clinical advancement of optogenetic therapy.

No MeSH data available.


Related in: MedlinePlus