Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients

Nguyen, Quan Dong; Schachar, Ronald A.; Nduaka, Chudy I.; Sperling, Marvin; Basile, Anthony S.; Klamerus, Karen J.; Chi-Burris, Katherine; Yan, Eric; Paggiarino, Dario A.; Rosenblatt, Irit; Khan, Atif Ahmed; Aitchison, Roger; Erlich, Shai

doi:10.1038/eye.2012.106

Cited by 68 publications

(39 citation statements)

References 14 publications

(13 reference statements)

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“…78 Clinical trials of intravitreal siRNA treatments, including those targeting RTP801, have reported safety and efficacy for ocular diseases. 48,50,86 Despite the inherent vulnerabilities of immunofluorescence-based analyses, such as antibody specificity and limitations of sampling for neuronal/glial quantification, both our in vivo and in vitro observations yielded consistent results. Here, we show that siRNA-mediated knockdown of RTP801 promotes RGC neuroprotection, supports elongation of regenerating axons after ONC in vivo, and potentiates a proregenerative reactive glial response to injury.…”

Section: Discussionsupporting

confidence: 65%

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Morgan-Warren

O'Neill

Cogan

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801.METHODS. Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a þ RGC survival, GFAP þ reactive gliosis, and GAP43 þ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. RESULTS. Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43þ axon regeneration at 400 to 1200 lm beyond the ONC site, and potentiated the reactive GFAP þ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP þ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity.CONCLUSIONS. The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

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Section: Discussionsupporting

confidence: 65%

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Morgan-Warren

O'Neill

Cogan

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Successful knock-down of VEGF receptor-1 (VEGFR1) after injection of naked stabilitymodified VEGFR1 siRNA has been demonstrated in mouse models (Shen et al, 2006). This route of administration is also currently being used in clinical trials with siRNAs targeting VEGF (Brucker, 2006), VEGFR1 (Kaiser et al, 2010) and hypoxia-inducible RTP801 genes (Nguyen et al, 2012b). As chemically modified siRNAs can also be degraded by vitreous endonucleases (Beverly et al, 2006), siRNA-based treatments of posterior segment diseases could require multiple intravitreal injections, similar to conventional treatments.…”

Section: Figurementioning

confidence: 99%

“…In addition, this siRNA targeting RTP801 gene is currently in clinical trials for the treatment of wet AMD. A phase I trial testing the efficacy and safety of stable, modified PF-655 administered alone by intravitreal injection (Nguyen et al, 2012b), and a phase II study (MONET) comparing PF-655 efficacy with that of ranibizumab as well as a ranibizumab/PF-655 combination therapy versus ranibizumab monotherapy (Nguyen et al, 2012c) have recently been performed (Table 1). The best-corrected visual acuity in AMD patients treated with PF-655 alone was less than that in the ranibizumab group.…”

Section: Age-related Macular Degenerationmentioning

confidence: 99%

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Guzmán-Aránguez

Loma

Pintor

2013

British J Pharmacology

109

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RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments. AbbreviationsAMD, age-related macular degeneration; Apaf-1, apoptotic protease-activating factor-1; CNV, choroidal neovascularization; CTGF, connective tissue growth factor; DR, diabetic retinopathy; dsRNA, double-stranded RNA; ECM, extracellular matrix; HIF-1α, hypoxia-inducible factor-1α; IOP, intraocular pressure; ONC, optic nerve crush; POAG, open-angle glaucoma; RGC, retinal ganglion cell; RISC, RNA-induced silencing complex; RNAi, RNA interference; RP, retinitis pigmentosa; Smad, signalling mathers against decapentaplegic; SPARC, secreted protein acidic and rich in cysteine; TLR3, toll-like receptor 3; TM, trabecular meshwork; TXNIP, thioredoxin interacting protein IntroductionRNA interference (RNAi) technology has been used to elucidate gene function, to generate model systems and to identify new molecular targets. In addition, RNAi is currently progressing from basic research to potential therapeutic applications. Because any gene that causes or contributes to a disease is susceptible to suppression by RNAi, RNAi therapy represents a promising biomedical strategy for treating a diverse range of diseases including cancer, cardiovascular diseases, neurodegenerative diseases, inflammatory conditions, viral infections and ocular diseases (Guo et al., 2010). In particular, the accessibility of the eye facilitates small-interfering RNA (siRNA) delivery, and naked siRNA has been efficiently applied by topical administration to the anterior segment or by intravitreal injection to the posterior segment (de Fougerolles, 2008). As the localized delivery of siRNA to the eye is less challenging than for other tissues, there has been significant progress made towards its use as a therapeutic procedure for eye diseases. In fact, several siRNA-based therapeutic agents for o...

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“…It was well tolerated without any significant safety issue. However, the limited sample size was not sufficient to statistically evaluate efficacy [149].…”

Section: 6age-related Macular Degenerationmentioning

confidence: 99%

Treatment of ocular disorders by gene therapy

Solinís

Pozo-Rodríguez

Apaolaza

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients

Abstract: Background To evaluate the safety, tolerability, pharmacokinetics, and dose-

Cited by 68 publications

References 14 publications

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Treatment of ocular disorders by gene therapy

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