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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

Retinal remodeling in human retinitis pigmentosa (RP). (a) Normal primate retina visualized with computational molecular phenotyping (Marc and Jones, 2002) using RGB = γ. TB.E mapping (gamma-aminobtyric acid; TB, toluidine blue; E, glutamate). OSL, outer segment layer; ELM, external limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; ILM, inner limiting membrane. (b) Cone-decimated advanced RP (Foundation Fighting Blindness Accession no. 133, 67-year-old female, no light perception, advanced simplex RP, 2.5 hours postmortem). RGB = E.G.J mapping (E, glutamate; G, glycine; J, glutathione). From Marc et al, 2003, by permission of the authors. RPE, retinal pigment epithelium; AC, amacrine cell; GC, ganglion cell. (c) Cone-sparing RP (University of Utah Lions Eye Bank, 21-year-old male, central vision only, 2 hours postmortem). Excitation mapping using 1-amino-4-guanidobutane (AGB) and 25 μM kainate stimulation (Marc and Jones, 2002) reveals aberrant iGluR (ionotropic glutamate receptor) excitation in surviving rod bipolar cells. RGB = G.B.E. mapping (G, glycine; B, AGB; E, glutamate). From Marc et al, 2007, by permission of the authors.
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Figure 3: Retinal remodeling in human retinitis pigmentosa (RP). (a) Normal primate retina visualized with computational molecular phenotyping (Marc and Jones, 2002) using RGB = γ. TB.E mapping (gamma-aminobtyric acid; TB, toluidine blue; E, glutamate). OSL, outer segment layer; ELM, external limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; ILM, inner limiting membrane. (b) Cone-decimated advanced RP (Foundation Fighting Blindness Accession no. 133, 67-year-old female, no light perception, advanced simplex RP, 2.5 hours postmortem). RGB = E.G.J mapping (E, glutamate; G, glycine; J, glutathione). From Marc et al, 2003, by permission of the authors. RPE, retinal pigment epithelium; AC, amacrine cell; GC, ganglion cell. (c) Cone-sparing RP (University of Utah Lions Eye Bank, 21-year-old male, central vision only, 2 hours postmortem). Excitation mapping using 1-amino-4-guanidobutane (AGB) and 25 μM kainate stimulation (Marc and Jones, 2002) reveals aberrant iGluR (ionotropic glutamate receptor) excitation in surviving rod bipolar cells. RGB = G.B.E. mapping (G, glycine; B, AGB; E, glutamate). From Marc et al, 2007, by permission of the authors.

Mentions: In Phase I, stressed photoreceptor cells rapidly change their synaptic associations with downstream retinal bipolar cells. In Phase II, photoreceptor cell death peaks, leading to the decimation of the outer nuclear layer truncation of bipolar cell dendrites, and the formation of the distal glial seal that completely separates the remnant neural retina from the surviving RP and choroid. This glial seal is formed by remnant Müller cell microvilli cross-linked by homocellular intermediate junctions and is not a glial scar like those formed by GFAP + astrocytes in damaged neuropil of the central nervous system. In cone sparing forms of RP near the macula, surviving rod bipolar cells reprogram their signaling from their classical mGluR6-based ON polarity to an iGluR-based OFF polarity.[50] Phase III is a persistent state of neural and glial remodeling, with progressive cell death, aberrant neuritogenesis, rewiring of all classes of neurons including the formation of pathologic synaptic microneuromas, pathologic neuronal migration of ganglion and amacrine cells to distal retina, and bipolar cell and amacrine cell migration to proximal retina. Further, retinal pigment epithelial cells begin to invade the neural retina, often descending completely to the inner limiting membrane. This generates the appearance of sharply delineated bone spicules. When this presentation is seen in ophthalmoscopy [Figure 2], it means that the retina is already in a state of advanced Phase III remodeling [Figure 3], and optogenetics or any other interventions will be largely ineffective. Figure 3b shows the effect of remodeling in a human retina, including absence of ganglion cells, virtually complete depletion of bipolar cells, and severe reorganization of the remnant neural retina through neuronal migration and glial hypertrophy. Figure 3c demonstrates rod bipolar cell reprogramming in human cone-sparing RP. Importantly, the spared cones often lack opsin expression, but retain some synaptic connectivity. Finally, Phase III Müller cells begin to chaotically reprogram into varied states of altered glutamine metabolism, implying that glial support of the essential glutamate cycle may be compromised.[53]


Optogenetics for retinal disorders.

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

Retinal remodeling in human retinitis pigmentosa (RP). (a) Normal primate retina visualized with computational molecular phenotyping (Marc and Jones, 2002) using RGB = γ. TB.E mapping (gamma-aminobtyric acid; TB, toluidine blue; E, glutamate). OSL, outer segment layer; ELM, external limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; ILM, inner limiting membrane. (b) Cone-decimated advanced RP (Foundation Fighting Blindness Accession no. 133, 67-year-old female, no light perception, advanced simplex RP, 2.5 hours postmortem). RGB = E.G.J mapping (E, glutamate; G, glycine; J, glutathione). From Marc et al, 2003, by permission of the authors. RPE, retinal pigment epithelium; AC, amacrine cell; GC, ganglion cell. (c) Cone-sparing RP (University of Utah Lions Eye Bank, 21-year-old male, central vision only, 2 hours postmortem). Excitation mapping using 1-amino-4-guanidobutane (AGB) and 25 μM kainate stimulation (Marc and Jones, 2002) reveals aberrant iGluR (ionotropic glutamate receptor) excitation in surviving rod bipolar cells. RGB = G.B.E. mapping (G, glycine; B, AGB; E, glutamate). From Marc et al, 2007, by permission of the authors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Retinal remodeling in human retinitis pigmentosa (RP). (a) Normal primate retina visualized with computational molecular phenotyping (Marc and Jones, 2002) using RGB = γ. TB.E mapping (gamma-aminobtyric acid; TB, toluidine blue; E, glutamate). OSL, outer segment layer; ELM, external limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; ILM, inner limiting membrane. (b) Cone-decimated advanced RP (Foundation Fighting Blindness Accession no. 133, 67-year-old female, no light perception, advanced simplex RP, 2.5 hours postmortem). RGB = E.G.J mapping (E, glutamate; G, glycine; J, glutathione). From Marc et al, 2003, by permission of the authors. RPE, retinal pigment epithelium; AC, amacrine cell; GC, ganglion cell. (c) Cone-sparing RP (University of Utah Lions Eye Bank, 21-year-old male, central vision only, 2 hours postmortem). Excitation mapping using 1-amino-4-guanidobutane (AGB) and 25 μM kainate stimulation (Marc and Jones, 2002) reveals aberrant iGluR (ionotropic glutamate receptor) excitation in surviving rod bipolar cells. RGB = G.B.E. mapping (G, glycine; B, AGB; E, glutamate). From Marc et al, 2007, by permission of the authors.
Mentions: In Phase I, stressed photoreceptor cells rapidly change their synaptic associations with downstream retinal bipolar cells. In Phase II, photoreceptor cell death peaks, leading to the decimation of the outer nuclear layer truncation of bipolar cell dendrites, and the formation of the distal glial seal that completely separates the remnant neural retina from the surviving RP and choroid. This glial seal is formed by remnant Müller cell microvilli cross-linked by homocellular intermediate junctions and is not a glial scar like those formed by GFAP + astrocytes in damaged neuropil of the central nervous system. In cone sparing forms of RP near the macula, surviving rod bipolar cells reprogram their signaling from their classical mGluR6-based ON polarity to an iGluR-based OFF polarity.[50] Phase III is a persistent state of neural and glial remodeling, with progressive cell death, aberrant neuritogenesis, rewiring of all classes of neurons including the formation of pathologic synaptic microneuromas, pathologic neuronal migration of ganglion and amacrine cells to distal retina, and bipolar cell and amacrine cell migration to proximal retina. Further, retinal pigment epithelial cells begin to invade the neural retina, often descending completely to the inner limiting membrane. This generates the appearance of sharply delineated bone spicules. When this presentation is seen in ophthalmoscopy [Figure 2], it means that the retina is already in a state of advanced Phase III remodeling [Figure 3], and optogenetics or any other interventions will be largely ineffective. Figure 3b shows the effect of remodeling in a human retina, including absence of ganglion cells, virtually complete depletion of bipolar cells, and severe reorganization of the remnant neural retina through neuronal migration and glial hypertrophy. Figure 3c demonstrates rod bipolar cell reprogramming in human cone-sparing RP. Importantly, the spared cones often lack opsin expression, but retain some synaptic connectivity. Finally, Phase III Müller cells begin to chaotically reprogram into varied states of altered glutamine metabolism, implying that glial support of the essential glutamate cycle may be compromised.[53]

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