Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis

Nakahara, Tsutomu; Morita, Akane; Yagasaki, Rina; Mori, Akira; Sakamoto, Kenji

doi:10.1248/bpb.b17-00475

Cited by 32 publications

(23 citation statements)

References 37 publications

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“…2 One proposed therapeutic target is the mTOR. 6 An essential constituent component of a number of cellular pathways, 9 mTOR is well-suited to address various aspects of these conditions via the modulation of growth factors, inflammatory processes, and downstream regulators of angiogenesis. 27 Among the latter is HIF-1α, which is mediated by mTORC1 to induce VEGF production 33 and subsequent neovascularization.…”

Section: Discussionmentioning

confidence: 99%

“…1 Therefore anti-VEGF therapeutic strategies have been pursued and approved to treat these conditions, 2,4 and are administered via repeated intravitreal injections, depending on the dosing schedule. Patient compliance is often negatively affected by the frequency of these injections, 5 and with safety questions having been raised 6,7 regarding the long-term inhibition of VEGF, the development of a gene therapeutic focused on a non-VEGF target may prove to be greatly beneficial.…”

mentioning

confidence: 99%

“…One such therapeutic target that has previously been set forth is mechanistic target of rapamycin (mTOR), 6,8 so named because it is targeted by the broadly antiproliferative rapamycin. 9 A serine/threonine kinase, mTOR exists as a component member of three separate complexes, mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), 9 and the recently identified mTOR complex 3 (mTORC3).…”

mentioning

confidence: 99%

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Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Lee

Chang²,

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee SHS, Chang H, Kim JH, et al. Inhibition of mTOR via an AAV-Delivered shRNA tested in a rat OIR model as a potential antiangiogenic gene therapy. Invest Ophthalmol Vis Sci. 2020;61(2):45. https://doi.org/10.1167/iovs.61.2.45 PURPOSE.Recent studies have shown that inhibitors of the mechanistic target of rapamycin (mTOR) play important roles in proliferating endothelial cells within the retinal vasculature. Here we explore the effects of inhibiting mTOR as a potential gene therapeutic against pathological retinal angiogenesis in a rat model of oxygen-induced retinopathy (OIR). METHODS.Sprague-Dawley pups were used to generate the OIR model, with a recombinant adeno-associated virus expressing an shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection on returning the rats to normoxia, with appropriate controls. Immunohistochemistry and TUNEL assays, as well as fluorescein angiography, were performed on transverse retinal sections and flat mounts, respectively, to determine the in vivo effects of mTOR inhibition. RESULTS.Compared with normal control rats, as well as OIR model animals that were either untreated (20.95 ± 6.85), mock-treated (14.50 ± 2.47), or injected with a control short hairpin RNA (shRNA)-containing virus vector (16.64 ± 4.92), rAAV2-shmTOR-GFP (4.28 ± 2.86, P = 0.00103) treatment resulted in dramatically reduced neovascularization as a percentage of total retinal area. These results mirrored quantifications of retinal avascular area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly greater therapeutic efficacy than the other treatments. The virus vector was additionally shown to reduce inflammatory cell infiltration into retinal tissue and possess antiapoptotic properties, both these processes having been implicated in the pathophysiology of angiogenic retinal disorders. CONCLUSIONS.Taken together, these results demonstrate the strong promise of rAAV2-shmTOR-GFP as an effective and convenient gene therapy for the treatment of neovascular retinal diseases.

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Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Lee

Chang²,

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Deptor gene encodes DEP Domain-Containing mTOR-Interacting Protein, which is a negative regulator of mammalian target of rapamycin (mTOR) signaling pathways. The mTOR-signaling pathways were previously shown to be profoundly interrelated with several mechanisms crucial for retinopathy progression, including oxidative stress, inflammation, hypoxia, angiogenesis, and proliferation/fibrosis, 35,36 Therefore, decreased Deptor gene expression in both blood mononuclear cells and retina might not only mark encountered oxidative stress, but also indicate effects of mTOR-signaling pathway overactivation, including neovascularization.…”

Section: Discussionmentioning

confidence: 99%

Short- and long-term impact of hyperoxia on the blood and retinal cells’ transcriptome in a mouse model of oxygen-induced retinopathy

et al. 2019

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BACKGROUND: We aimed to identify global blood and retinal gene expression patterns in murine oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity, which may allow better understanding of the pathogenesis of this severe ocular prematurity complication and identification of potential blood biomarkers. METHODS: A total of 120 C57BL/6J mice were randomly divided into an OIR group, in which 7-day-old pups were maintained in 75% oxygen for 5 days, or a control group. RNA was extracted from the whole-blood mononuclear cells and retinal cells on days 12, 17, and 28. Gene expression in the RNA samples was evaluated with mouse gene expression microarrays. RESULTS: There were 38, 1370 and 111 genes, the expression of which differed between the OIR and control retinas on days 12, 17, and 28, respectively. Gene expression in the blood mononuclear cells was significantly altered only on day 17. Deptor and Nol4 genes showed reduced expression both in the blood and retinal cells on day 17. CONCLUSION: There are sustained marked changes in the global pattern of gene expression in the OIR mice retinas. An altered expression of Deptor and Nol4 genes in the blood mononuclear cells requires further investigation as they may indicate retinal neovascularization.

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“…Among these are drugs targeting a central regulator, such as Raf kinase, mammalian target of rapamycin (mTOR) and the RTP 801 gene. [274][275][276] A Phase I/II study of an ankyrin repeat protein that binds VEGF reduced DME when injected intravitreally in several patients with a duration of effect of 8-12 weeks but had a tendency to cause iritis. 277 A modified version designed to eliminate the problem of iritis is undergoing further clinical testing.…”

Section: Future Trends Diagnosticsmentioning

confidence: 99%

<p>The Evolving Treatment of Diabetic Retinopathy</p>

Mansour¹,

Browning²,

Wong³

et al. 2020

OPTH

177

119

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Purpose: To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. Methods: A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. Results: Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. Conclusion: Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and ...

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Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis

Cited by 32 publications

References 37 publications

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Short- and long-term impact of hyperoxia on the blood and retinal cells’ transcriptome in a mouse model of oxygen-induced retinopathy

<p>The Evolving Treatment of Diabetic Retinopathy</p>

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