Inner Retinal Abnormalities in X-linked Retinitis Pigmentosa with RPGR Mutations

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.4). 11/2007; 48(10):4759-65. DOI: 10.1167/iovs.07-0453
Source: PubMed


To investigate in vivo the retinal microstructure in X-linked retinitis pigmentosa (XLRP) caused by RPGR mutations as a prelude to treatment initiatives for this common form of RP.
Patients with RPGR-XLRP (n = 12; age range, 10-56 years) were studied by optical coherence tomography (OCT) in a wide region of central retina. Overall retinal thickness and outer nuclear layer (ONL) and inner retinal parameters across horizontal and vertical meridians were analyzed and compared.
Retinal architecture of all patients with RPGR mutations was abnormal. At the fovea in younger patients, the ONL could be normal; but, at increasing eccentricities, there was a loss of photoreceptor laminar structure, even at the youngest ages studied. At later ages and advanced disease stages, the ONL was thin and reduced in extent. Inner retinal thickness, in contrast, was normal or hyperthick. Inner retinal thickening was detectable at all ages studied and was strongly associated with ONL loss.
Inner retinal laminar abnormalities in RPGR-XLRP are likely to reflect a neuronal-glial retinal remodeling response to photoreceptor loss and are detectable relatively early in the disease course. These results should be factored into emerging therapeutic strategies for this form of RP.

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Available from: Artur Cideciyan, Sep 30, 2015
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    • "RPGR overexpression in the WT retina will also inform as to whether similar gene therapy intervention could be safely considered for some carrier female patients. Finally, pursuing detailed phenotypic characterization of XLRP patients (Jacobson et al. 1997; Lorenz et al. 2003; Aleman et al. 2007; Huang et al. 2012) is necessary to establish valid outcome measures of therapeutic efficacy for future human clinical trials. "
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    ABSTRACT: X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is a severe and early onset form of retinal degeneration, and no treatment is currently available. Recent evidence in two clinically relevant canine models shows that adeno-associated viral (AAV)-mediated RPGR gene transfer to rods and cones can prevent disease onset and rescue photoreceptors at early- and mid-stages of degeneration. There is thus a strong incentive for conducting long-term, preclinical efficacy and safety studies, while concomitantly pursuing the detailed phenotypic characterization of XLRP disease in patients that may benefit from such corrective therapy.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(2). DOI:10.1101/cshperspect.a017392 · 9.47 Impact Factor
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    • "Rd9/Y mice exhibited larger b/a-wave ratios compared to wild-type at later ages, suggesting that photoreceptor cell dysfunction predominates over inner retinal changes. Inner retinal abnormalities in RPGR-XLRP have been documented in humans [51] and in dogs [28] in the form of thickening of inner retinal structures secondary to ONL loss. Although we did not perform cell counts, the inner retina and ganglion cell layers of the Rd9/Y male mice showed no obvious loss by light microscopy. "
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    ABSTRACT: Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are the most common cause of X-linked retinitis pigmentosa (XLRP) and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9) strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG) a- and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy.
    PLoS ONE 05/2012; 7(5):e35865. DOI:10.1371/journal.pone.0035865 · 3.23 Impact Factor
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    • "In humans and animals, inherited photoreceptor degeneration causes, with time, alterations in all retinal layers (Villegas-Pérez et al., 1996, 1998; Milam et al., 1998; Fariss et al., 2000; Wang et al., 2000, 2003, 2005; Jones et al., 2003; Cuenca et al., 2004; Jones and Marc., 2005; Aleman et al., 2007, 2008; Walia et al., 2007; Walia and Fishman, 2008). Patients with retinitis pigmentosa usually show optic disc pallor and, while some investigators have documented retinal ganglion cell (RGC) loss and thinning of the retinal nerve fiber layer in patients with retinitis pigmentosa (Stone et al., 1992; Santos et al., 1997; Walia et al., 2007; Lim et al., 2008; Walia and Fishman, 2008), other have failed to do so (Hood et al., 2009; Oishi et al., 2009). "
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    ABSTRACT: The P23H-1 rat strain carries a rhodopsin mutation frequently found in retinitis pigmentosa patients. We investigated the progressive degeneration of the inner retina in this strain, focussing on retinal ganglion cells (RGCs) fate. Our data show that photoreceptor death commences in the ventral retina, spreading to the whole retina as the rat ages. Quantification of the total number of RGCs identified by Fluorogold tracing and Brn3a expression, disclosed that the population of RGCs in young P23H rats is significantly smaller than in its homologous SD strain. In the mutant strain, there is also RGC loss with age: RGCs show their first symptoms of degeneration at P180, as revealed by an abnormal expression of cytoskeletal proteins which, at P365, translates into a significant loss of RGCs, that may ultimately be caused by displaced inner retinal vessels that drag and strangulate their axons. RGC axonal compression begins also in the ventral retina and spreads from there causing RGC loss through the whole retinal surface. These decaying processes are common to several models of photoreceptor loss, but show some differences between inherited and light-induced photoreceptor degeneration and should therefore be studied to a better understanding of photoreceptor degeneration and when developing therapies for these diseases.
    Experimental Eye Research 10/2010; 91(6):800-10. DOI:10.1016/j.exer.2010.10.003 · 2.71 Impact Factor
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