Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin, Gayle B.; Gogna, Navdeep; Chang, Bo; Damkham, Nattaya; Pinkney, Jai; Hyde, Lillian F.; Stone, Lisa; Naggert, Jürgen Κ.; Nishina, Patsy M.; Krebs, Mark P.

doi:10.3390/cells9040931

Cited by 66 publications

(60 citation statements)

References 493 publications

(598 reference statements)

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“…In RP rods die before cones, night-vision is lost early-on, and the visual field increasingly shrinks from the periphery to the center, until all photoreceptors die. The process can take years to decades in humans and weeks to months in different animal models (Collin et al, 2020;Winkler et al, 2020). Many different mutations in several different genes can cause RP.…”

Section: Introductionmentioning

confidence: 99%

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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Vision impairment and blindness in humans are most frequently caused by the degeneration and loss of photoreceptor cells in the outer retina, as is the case for age-related macular degeneration, retinitis pigmentosa, retinal detachment and many other diseases. While inner retinal neurons survive degeneration, they undergo fundamental pathophysiological changes, collectively known as “remodeling.” Inner retinal remodeling downstream to photoreceptor death occurs across mammalian retinas from mice to humans, independently of the cause of degeneration. It results in pervasive spontaneous hyperactivity and membrane hyperpermeability in retinal ganglion cells, which funnel all retinal signals to the brain. Remodeling reduces light detection in vision-impaired patients and precludes meaningful vision restoration in blind individuals. In this review, we summarize current hypotheses proposed to explain remodeling and their potential medical significance highlighting the important role played by retinoic acid and its receptor.

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Section: Introductionmentioning

confidence: 99%

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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“…The rate of retinal degeneration in humans and animal models of RP depends, in part, on the inciting gene defect 9 , 29 and likely correlates with the magnitude of microglial morphological activation. Light-inducible models with swift retinal degeneration, including the I307N Rho and arrestin −/− mice 26 , exhibit activated microglia with a qualitatively large size and a frank ameboid morphology, apparent on day three in our study.…”

Section: Discussionmentioning

confidence: 99%

Sectoral activation of glia in an inducible mouse model of autosomal dominant retinitis pigmentosa

Massengill

Ash

Young

et al. 2020

Sci Rep

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Retinitis pigmentosa (RP) is a group of blinding disorders caused by diverse mutations, including in rhodopsin (RHO). Effective therapies have yet to be discovered. The I307N Rho mouse is a light-inducible model of autosomal dominant RP. Our purpose was to describe the glial response in this mouse model to educate future experimentation. I307N Rho mice were exposed to 20,000 lx of light for thirty minutes to induce retinal degeneration. Immunofluorescence staining of cross-sections and flat-mounts was performed to visualize the response of microglia and Müller glia. Histology was correlated with spectral-domain optical coherence tomography imaging (SD-OCT). Microglia dendrites extended between photoreceptors within two hours of induction, withdrew their dendrites between twelve hours and one day, appeared ameboid by three days, and assumed a ramified morphology by one month. Glial activation was more robust in the inferior retina and modulated across the boundary of light damage. SD-OCT hyper-reflectivity overlapped with activated microglia. Finally, microglia transiently adhered to the RPE before which RPE cells appeared dysmorphic. Our data demonstrate the spatial and temporal pattern of glial activation in the I307N Rho mouse, and correlate these patterns with SD-OCT images, assisting in interpretation of SD-OCT images in preclinical models and in human RP.

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“…With FDA/EMA approval of Luxturna TM , the first ocular gene therapy in 2017/18, interest in development of gene therapies for IRDs is substantial. In preclinical proof of principle studies, animal models of IRDs ( Ziccardi et al, 2019 ; Collin et al, 2020 ) have been extremely useful and ultimately contributed to paving the way toward clinical trials for many retinal gene therapies ( ClinicalTrials.gov ); reviewed by Dalkara et al (2016) and Trapani and Auricchio (2019) . Many preclinical studies have highlighted the value of adeno associated virus (AAV) as a means of gene delivery and have demonstrated benefit at molecular, histological and functional levels of AAV-delivered gene therapies (among others, Millington-Ward et al, 2011 ; Chadderton et al, 2013 ; Schön et al, 2017 ; Cideciyan et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

AAV-Delivered Tulp1 Supplementation Therapy Targeting Photoreceptors Provides Minimal Benefit in Tulp1−/− Retinas

et al. 2020

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With marketing approval of the first ocular gene therapy, and other gene therapies in clinical trial, treatments for inherited retinal degenerations (IRDs) have become a reality. Biallelic mutations in the tubby like protein 1 gene ( TULP1 ) are causative of IRDs in humans; a mouse knock-out model ( Tulp1−/− ) is characterized by a similar disease phenotype. We developed a Tulp1 supplementation therapy for Tulp1−/− mice. Utilizing subretinal AAV2/5 delivery at postnatal day (p)2–3 and rhodopsin-kinase promoter ( GRK1P ) we targeted Tulp1 to photoreceptor cells exploring three doses, 2.2E9, 3.7E8, and 1.2E8 vgs. Tulp1 mRNA and TULP1 protein were assessed by RT-qPCR, western blot and immunocytochemistry, and visual function by electroretinography. Our results indicate that TULP1 was expressed in photoreceptors; achieved levels of Tulp1 mRNA and protein were similar to wild type levels at p20. However, the thickness of the outer nuclear layer (ONL) did not improve in treated Tulp1−/− mice. There was a small and transient electroretinography benefit in the treated retinas at 4 weeks of age (not observed by 6 weeks) when using 3.7E8 vg dose. Dark-adapted mixed rod and cone a- and b-wave amplitudes were 24.3 ± 13.5 μV and 52.2 ± 31.7 μV in treated Tulp1−/− mice, which were significantly different ( p < 0.001, t -test), from those detected in untreated eyes (7.1 ± 7.0 μV and 9.4 ± 15.1 μV, respectively). Our results indicate that Tulp1 supplementation in photoreceptors may not be sufficient to provide robust benefit in Tulp1−/− mice. As such, further studies are required to fine tune the Tulp1 supplementation therapy, which, in principle, should rescue the Tulp1−/− phenotype.

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Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Cited by 66 publications

References 493 publications

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

Sectoral activation of glia in an inducible mouse model of autosomal dominant retinitis pigmentosa

AAV-Delivered Tulp1 Supplementation Therapy Targeting Photoreceptors Provides Minimal Benefit in Tulp1−/− Retinas

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