Emerging Gene Therapies for Retinal Degenerations

Cepko, Constance L.

doi:10.1523/jneurosci.0295-12.2012

Cited by 32 publications

(21 citation statements)

References 69 publications

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“…While antioxidant gene therapy can be used as a standalone treatment, it can also supplement other gene therapies. It might be particularly useful in the case of optogenetic therapy (78). Dysfunctional cones in RP mouse models were shown to respond to light that activated an optogenetic protein, halorhodopsin, which was delivered by an AAV (79).…”

Section: Discussionmentioning

confidence: 99%

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

et al. 2015

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Section: Discussionmentioning

confidence: 99%

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

et al. 2015

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“…The potential use of the AAV-halorhodopsin extends earlier work with gene therapy treatment with AAV-RPE65 of children with another form of genetic blindness, Leber's congenital amaurosis, which is currently approved (Testa et al 2013). Alternatively, in the future a combination therapy of antioxidants, enzymes, and/or growth factors, and AAV-halorhodopsin might prolong cone survival and function (Cepko 2012). These exciting groundbreaking experiments that utilized the cone arrestin promoter are proof-of-principle examples toward realizing the therapeutic goal of restoring vision and demonstrate that expression and function of halorhodopsin in human cone photoreceptors are feasible.…”

Section: Potential Therapeutic Use Of Cone Arrestin Promotermentioning

confidence: 88%

Cone Arrestin: Deciphering the Structure and Functions of Arrestin 4 in Vision

Craft

Deming

2013

Arrestins - Pharmacology and Therapeutic Potential

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Cone arrestin (Arr4) was discovered 20 years ago as a human X-chromosomal gene that is highly expressed in pinealocytes and cone photoreceptors. Subsequently, specific antibodies were developed to identify Arr4 and to distinguish cone photoreceptor morphology in health and disease states. These reagents were used to demonstrate Arr4 translocation from cone inner segments in the dark to outer segments with light stimulation, similarly to Arrestin 1 (Arr1) translocation in rod photoreceptors. A decade later, the Arr4 crystal structure was solved, which provided more clues about Arr4's mechanisms of action. With the creation of genetically engineered visual arrestin knockout mice, one critical function of Arr4 was clarified. In single living cones, both visual arrestins bind to light-activated, G protein receptor kinase 1 (Grk1) phosphorylated cone opsins to desensitize them, and in their absence, mouse cone pigment shutoff is delayed. Still under investigation are additional functions; however, it is clear that Arr4 has non-opsin-binding partners and diverse synaptic roles, including cellular anchoring and trafficking. Recent studies reveal Arr4 is involved in high temporal resolution and contrast sensitivity, which opens up a new direction for research on this intriguing protein. Even more exciting is the potential for therapeutic use of the Arr4 promoter with an AAV-halorhodopsin that was shown to be effective in using the remaining cones in retinal degeneration mouse models to drive inner retinal circuitry for motion detection and light/dark discrimination.

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“…Indeed this so-called bystander, non-cell-autonomous effect is both the most significant characteristic of RP from the point of view of clinical relevance and a fascinating biological enigma, presently an area of active investigation (Cepko, 2012;Sahel and Roska, 2013;Sahni et al, 2011). Among postulated causes of cone secondary death are oxidative stress, release of toxic factors from dying, nearby cells, lack of survival factors normally released by rods, metabolic impairment and starvation of cones themselves.…”

Section: Retinitis Pigmentosamentioning

confidence: 99%

“…Various excellent reviews have been published on the subject to which the reader is addressed (Boye et al, 2013;Cepko, 2012;Dalkara et al, 2015;Pierce and Bennett, 2015;Sahel and Roska, 2013). Obviously, the success of LCA gene therapy has encouraged exploiting this strategy for RP and for other retinal genetic disorders.…”

Section: Gene Therapymentioning

confidence: 99%