A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration

Cashman, Siobhan M.; Ramo, Kasmir; Kumar‐Singh, Rajendra

doi:10.1371/journal.pone.0019078

Cited by 112 publications

(122 citation statements)

References 38 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Although effective treatments exist to temporize the "wet" form of AMD associated with choroidal neovascularization (36)(37)(38)(39), no effective treatments exist for the early "dry" form of AMD that more closely resembles STGD1.…”

Section: Significancementioning

confidence: 99%

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

Lenis

Sarfare

Jiang

et al. 2017

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

View full text Add to dashboard Cite

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4 −/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRYtreated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY-treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.recessive Stargardt macular degeneration | complement system | retinal pigment epithelium | bisretinoids | gene therapy R ecessive Stargardt macular degeneration (STGD1) is a blinding disease of children and young adults caused by mutations in the ATP binding cassette subfamily A member 4 (ABCA4) gene (1, 2). The pathological hallmark of STGD1 is deposition of autofluorescent lipofuscin in the retinal pigment epithelium (RPE), which precedes photoreceptor degeneration (3, 4). The exact mechanism of how RPE lipofuscin accumulation disrupts overall RPE performance is poorly understood. The RPE fulfills several photoreceptor support tasks, including phagocytosis of distal outer segments (OS) and processing of visual retinoids (5-8). In addition, the RPE plays a major role in controlling the ocular immune response through expression of various complement negative regulatory proteins (CRPs) (9). For these reasons, photoreceptors are critically dependent on a healthy RPE for continued viability.The ABCA4 transporter clears retinaldehyde released by photobleached rhodopsin and cone-opsins from OS discs in the form of N-retinylidene phosphatidylethanolamine (N-ret-PE) (10). As a result, mice lacking ABCA4 accumulate retinaldehyde and N-ret-PE in their OS after light exposu...

show abstract

Section: Significancementioning

confidence: 99%

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

Lenis

Sarfare

Jiang

et al. 2017

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

View full text Add to dashboard Cite

show abstract

“…The same group subsequently used the same technique to deliver the gene vector distal to the site of CNV with similar inhibitory effects. Encouragingly, the benefit was also preserved with less invasive intravitreal delivery (Cashman et al 2011b). Clinical trials using CD59 delivered either directly or via gene therapy are awaited.…”

Section: Other Complement Regulatorsmentioning

confidence: 99%

Age-related macular degeneration and the complement system

et al. 2012

View full text Add to dashboard Cite

“…In as over-expression of proteins in corneal epithelium of patients with diabetes mellitus, but their application for inherited gene defects is discouraged [30,31]. Nevertheless, Ads have demonstrated transfection efficacy both in anterior [10,[32][33][34][35] and posterior eye segment [36][37][38][39].…”

Section: Delivery Systemsmentioning

confidence: 99%

“…rAds are also able to transfect trabecular meshwork, which is interesting to treat glaucoma and steroid-induced IOP [10,34,35]. Regarding retinaassociated diseases, rAds have been designed as vectors for genes involved in retinitis pigmentosa [36], age-related macular degeneration [37,38], or diabetic retinopathies [39].…”

Section: Delivery Systemsmentioning

confidence: 99%