Gene Therapy for PRPH2-Associated Ocular Disease: Challenges and Prospects

Conley, Shannon M.; Naash, Muna I.

doi:10.1101/cshperspect.a017376

Cited by 40 publications

(37 citation statements)

References 88 publications

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“…The development of mutation-independent gene knockdown-andreplacement approaches have been explored for the treatment of dominantly inherited systemic and retinal diseases that result from toxic gain-of-function mutations and/or to circumvent high mutational heterogeneity (40-43, 52, 53). A significant challenge that likely has delayed the development of clinical therapies is the need to successfully fine-tune the level of reduction of both mutant and WT endogenous proteins while providing sufficient resistant replacement (54). Here, we show in a naturally occurring large animal form of RHO-adRP that this dual-function strategy can effectively provide long-term photoreceptor pres-ervation.…”

Section: Discussionmentioning

confidence: 90%

Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

Cideciyan

Sudharsan

Dufour

et al. 2018

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

117

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Inherited retinal degenerations are caused by mutations in >250 genes that affect photoreceptor cells or the retinal pigment epithelium and result in vision loss. For autosomal recessive and X-linked retinal degenerations, significant progress has been achieved in the field of gene therapy as evidenced by the growing number of clinical trials and the recent commercialization of the first gene therapy for a form of congenital blindness. However, despite significant efforts to develop a treatment for the most common form of autosomal dominant retinitis pigmentosa (adRP) caused by >150 mutations in the rhodopsin () gene, translation to the clinic has stalled. Here, we identified a highly efficient shRNA that targets human (and canine) in a mutation-independent manner. In a single adeno-associated viral (AAV) vector we combined this shRNA with a human replacement cDNA made resistant to RNA interference and tested this construct in a naturally occurring canine model of -adRP. Subretinal vector injections led to nearly complete suppression of endogenous canine RNA, while the human replacement cDNA resulted in up to 30% of normal RHO protein levels. Noninvasive retinal imaging showed photoreceptors in treated areas were completely protected from retinal degeneration. Histopathology confirmed retention of normal photoreceptor structure and RHO expression in rod outer segments. Long-term (>8 mo) follow-up by retinal imaging and electroretinography indicated stable structural and functional preservation. The efficacy of this gene therapy in a clinically relevant large-animal model paves the way for treating patients with -adRP.

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Section: Discussionmentioning

confidence: 90%

Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

Cideciyan

Sudharsan

Dufour

et al. 2018

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

117

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“…101–103 Improving the biological infrastructure of the implanted auditory system could enhance the capacity to receive and process sensory information, allowing more patient-specific stimulation strategies, and might ultimately obviate the need for cochlear implantation. 104 …”

Section: Future Directionsmentioning

confidence: 99%

Neurocognitive factors in sensory restoration of early deafness: a connectome model

Kral

Kronenberger

Pisoni

et al. 2016

The Lancet Neurology

268

240

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Progress in biomedical technology (cochlear, vestibular, and retinal implants) has led to remarkable success in neurosensory restoration, particularly in the auditory system. However, outcomes vary considerably, even after accounting for comorbidity—for example, after cochlear implantation, some deaf children develop spoken language skills approaching those of their hearing peers, whereas other children fail to do so. Here, we review evidence that auditory deprivation has widespread effects on brain development, affecting the capacity to process information beyond the auditory system. After sensory loss and deafness, the brain’s effective connectivity is altered within the auditory system, between sensory systems, and between the auditory system and centres serving higher order neurocognitive functions. As a result, congenital sensory loss could be thought of as a connectome disease, with interindividual variability in the brain’s adaptation to sensory loss underpinning much of the observed variation in outcome of cochlear implantation. Different executive functions, sequential processing, and concept formation are at particular risk in deaf children. A battery of clinical tests can allow early identification of neurocognitive risk factors. Intervention strategies that address these impairments with a personalised approach, taking interindividual variations into account, will further improve outcomes.

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“…Nanoparticles (NP) represent a second promising approach in transferring WT Prph2. These particles were found to be well tolerated by the retina, even after multiple injections, and have a high DNA capacity up to 14 kb, as tested in the eye [115][116][117][118][119][120]. NP carrying full-length murine Prph2 cDNA under the control of either rod or cone specific IRBP promoters or ubiquitous chicken beta actin promoter was injected in the retina of Prph2 +/− mice [121].…”

Section: Gene Therapy Of Prph2 Mutationsmentioning

confidence: 99%

The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases

Tebbe

Kakakhel

Makia

et al. 2020

Cells

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Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. Although the exact role of Rom1 has not been well studied, it has been concluded that it is not necessary for disc morphogenesis but is required for fine tuning OS disc size and structure. Pathogenic mutations in PRPH2 often result in complex and multifactorial phenotypes, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium (RPE) and retinal/choroidal vasculature. The ability of Prph2 to form complexes was identified as a key requirement for the development and maintenance of OS structure and function. Studies using mouse models of pathogenic Prph2 mutations established a connection between changes in complex formation and disease phenotypes. Although progress has been made in the development of therapeutic approaches for retinal diseases in general, the highly complex interplay of functions mediated by Prph2 and the precise regulation of these complexes made it difficult, thus far, to develop a suitable Prph2-specific therapy. Here we describe the latest results obtained in Prph2-associated research and how mouse models provided new insights into the pathogenesis of its related diseases. Furthermore, we give an overview on the current status of the development of therapeutic solutions.

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Gene Therapy for PRPH2-Associated Ocular Disease: Challenges and Prospects

Cited by 40 publications

References 88 publications

Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

Neurocognitive factors in sensory restoration of early deafness: a connectome model

The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases

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