Neural Reprogramming in Retinal Degeneration

Marc, Robert E.; Jones, Bryan W.; Anderson, James R.; Kinard, Krista; Marshak, David; Wilson, John H.; Wensel, Theodore G.; Lucas, Robert J.

doi:10.1167/iovs.07-0032

Cited by 277 publications

(401 citation statements)

References 28 publications

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“…RGCs are well-suited therapy targets for late-stage disease because they have been shown to stay morphologically intact (4) with minimal remodeling following photoreceptor degeneration compared with the other retinal cells (27). Furthermore, RGCs are easily targeted due to their proximity to the vitreous, enabling strong, uniform, and widespread expression after intravitreal injection of AAV vectors.…”

Section: Discussionmentioning

confidence: 99%

“…Single-unit RGC responses from ON-BC LiGluR-MAG0 460 in both rd1 and rd10 resembled the RGC responses seen in wt retina more closely than RGC LiGluR-MAG0 460 . ON-BCs might therefore be the target of choice in early stages of retinal degeneration, before substantial synaptic remodeling has occurred (27). In late stages of retinal degeneration with severe circuit degeneration, it may be preferable to target the least affected cells, the RGCs, to generate a strong and synchronized output signal.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

Gaub

Berry²,

Holt³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

104

137

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Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second-and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0 460 ). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform lightevoked firing when LiGluR-MAG0 460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0 460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0 460 in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rodcone dystrophy dog model of blindness, LiGluR-MAG0 460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0 460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.retinal gene therapy | visual prosthetics | retinitis pigmentosa | optogenetic pharmacology | azobenzene photoswitches

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

Gaub

Berry²,

Holt³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

104

137

View full text Add to dashboard Cite

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“…RGC loss is a feature of many degenerative ophthalmic conditions, 28 and there is also ongoing, often aberrant, remodelling of intraretinal circuitry as a consequence of photoreceptor loss. 56,57 Use of appropriate AAV vectors may prevent or reduce such anomalous reorganizations within the inner nuclear layer, potentially enhancing the effectiveness of other therapies such as cellular or bionic implants. 57 Finally, new vector constructs, different modes of delivery, 24,25 and the isolation and modification of different serotypes 7,58-62 will lead to novel vectors that have greater packaging capacity 33,63 and cell specificity, and may even further minimize immunological sequelae following therapeutic application.…”

Section: Discussionmentioning

confidence: 99%

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

et al. 2008

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Recombinant adeno-associated virus (rAAV) vectors are increasingly being used as tools for gene therapy, and clinical trials have begun in patients with genetically linked retinal disorders. Intravitreal injection is optimal for the transduction of retinal ganglion cells (RGCs), although complete selectivity has not been achieved. There may also be advantages in using intravitreal approaches for the transduction of photoreceptors. Here we compared the cellular tropism and transduction efficiency of rAAV2/1, -2/2, -2/3, -2/4, -2/5, -2/6 and -2/8 in adult rat retina after intravitreal injection. Each vector encoded green fluorescent protein (GFP), and the number, laminar distribution and morphology of transduced GFP + cells were determined using fluorescent microscopy. Assessment of transduced cell phenotype was based on cell morphology and immunohistochemistry. rAAV2/2 and rAAV2/6 transduced the greatest number of cells, whereas rAAV2/5 and rAAV2/8 were least efficient. Most vectors primarily transduced RGCs; however, rAAV2/6 had a more diverse tropism profile, with 46% identified as amacrine or bipolar cells, 23% as RGCs and 22% as Mü ller cells. Mü ller cells were also frequently transduced by rAAV2/4. The highest photoreceptor transduction was seen after intravitreal rAAV2/3 injection. These data facilitate the design and selection of rAAV vectors to target specific retinal cells, potentially leading to an improved gene therapy for various human retinal pathologies.

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“…Because all these strategies aim to stimulate remnant retinal circuits in the degenerate retina, it has become imperative to understand how neural circuits remodel in response to photoreceptor death (Marc et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

Borowska¹,

Trenholm²,

Awatramani³

2011

J. Neurosci.

106

171

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The loss of photoreceptors during retinal degeneration (RD) is known to lead to an increase in basal activity in remnant neural networks. To identify the source of activity, we combined two-photon imaging with patch-clamp techniques to examine the physiological properties of morphologically identified retinal neurons in a mouse model of RD (rd1). Analysis of activity in rd1 ganglion cells revealed sustained oscillatory (ϳ10 Hz) synaptic activity in ϳ30% of all classes of cells. Oscillatory activity persisted after putative inputs from residual photoreceptor, rod bipolar cell, and inhibitory amacrine cell synapses were pharmacologically blocked, suggesting that presynaptic cone bipolar cells were intrinsically active. Examination of presynaptic rd1 ON and OFF bipolar cells indicated that they rested at relatively negative potentials (less than Ϫ50 mV). However, in approximately half the cone bipolar cells, low-amplitude membrane oscillation (ϳ5 mV, ϳ10 Hz) were apparent. Such oscillations were also observed in AII amacrine cells. Oscillations in ON cone bipolar and AII amacrine cells exhibited a weak apparent voltage dependence and were resistant to blockade of synaptic receptors, suggesting that, as in wild-type retina, they form an electrically coupled network. In addition, oscillations were insensitive to blockers of voltage-gated Ca 2ϩ channels (0.5 mM Cd 2ϩ and 0.5 mM Ni 2ϩ ), ruling out known mechanisms that underlie oscillatory behavior in bipolar cells. Together, these results indicate that an electrically coupled network of ON cone bipolar/AII amacrine cells constitutes an intrinsic oscillator in the rd1 retina that is likely to drive synaptic activity in downstream circuits.

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Neural Reprogramming in Retinal Degeneration

Cited by 277 publications

References 28 publications

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

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