Photoreceptor degeneration by intravitreal injection of N-methyl-N-nitrosourea (MNU) in rabbits: a pilot study

Rösch, Sarah; Werner, Claudia; Müller, Frank; Walter, Peter

doi:10.1007/s00417-016-3531-7

Cited by 18 publications

(17 citation statements)

References 26 publications

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“…According to the investigators, since injected SI may not be evenly distributed in the vitreous due to its uneven liquefaction characteristics, uneven retinal degeneration is caused. Another photoreceptor degeneration rabbit model produced by intravitreal injection of N-methyl-N-nitrosourea showed selective but inconsistent photoreceptor degeneration [ 152 ]. Subretinally injected hESC-RPE in immunosuppressed SI-induced RD rabbits failed to integrate into the areas that showed geographic atrophy-like symptoms [ 153 ].…”

Section: Animal Models For Stem Cell-based Therapiesmentioning

confidence: 99%

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

Lin

Seiler

Zhu

et al. 2017

Stem Cells International

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Dysfunction and death of retinal pigment epithelium (RPE) and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an "immune privileged" site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula). Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors) into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed.

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Section: Animal Models For Stem Cell-based Therapiesmentioning

confidence: 99%

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

Lin

Seiler

Zhu

et al. 2017

Stem Cells International

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“… 4 N-methyl-N-nitrosourea (MNU), as an alkylating carcinogen, is capable of mediating selective photoreceptor apoptosis in mammalian retinas, thereby generating a pharmacologically induced animal model of RD. 5 , 6 After a single systemic administration, MNU toxicity induces active signs of RD, such as decreased outer nuclear layer (ONL) thickness, impaired electroretinogram (ERG) response, and hyper-expressed apoptotic labeling. Generally, this degenerative process in mouse retina is accomplished within 7 days with the administered dose of 60 mg/kg.…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus-mediated neuroglobin overexpression ameliorates the N-methyl-N-nitrosourea-induced retinal impairments: a novel therapeutic strategy against photoreceptor degeneration

Tao

Yang

Wei

et al. 2017

TCRM

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Retinal degeneration (RD) is a heterogeneous group of inherited dystrophies leading to blindness. The N-methyl-N-nitrosourea (MNU)-administered mouse is used as a pharmacologically induced RD animal model in various therapeutic investigations. The present study found the retinal neuroglobin (NGB) expression in the MNU-administered mice was significantly lower than in normal controls, suggesting NGB was correlated with RD. Subsequently, an adeno-associated virus (AAV)-2-mCMV-NGB vector was delivered into the subretinal space of the MNU-administered mice. The retinal NGB expression of the treated eye was upregulated significantly in both protein and mRNA levels. Further, we found NGB overexpression could alleviate visual impairments and morphological devastations in MNU-administered mice. NGB overexpression could rectify apoptotic abnormalities and ameliorate oxidative stress in MNU-administered mice, thereby promoting photoreceptor survival. The cone photoreceptors in MNU-administered mice were also sensitive to AAV-mediated NGB overexpression. Taken together, our findings suggest that manipulating NGB bioactivity via gene therapy may represent a novel therapeutic strategy against RD. Future elucidation of the exact role of NGB would advance our knowledge about the pathological mechanisms underlying RD.

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“…xed location, because the nal concentration of retinotoxic agents which diffused through the vitreous and cross the entire retina to reach the photoreceptors after intravitreal injection was not even across the whole retina [21,29]. For solving the above issues, the present study used SI to induce lesion-controllable retinal damage by delivering SNP to the target location with accurate concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Retinal degenerative conditions in large-sized animals such as cats, rabbits, pigs and monkeys have been induced by several approaches including laser or severe light exposure, and retinotoxic reagents [15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

“…However, some limitations exist in these models. For instance, laser or light exposure caused focal damage of retina with small lesion size or unconsistent damage degree [18,19]; intravenous injection of retinotoxic agents such as sodium iodate and N-methyl-N-nitrosourea (MNU) led to systemic complications with high mortality, while intravitreous injection of the above agents caused uncontrollable or random distribution of retinal lesions [13,[20][21][22]. A new method of subretinal injection (SI) has been applied to deliver cobalt chloride to induce a lesion-controllable RP model in monkeys for retinal sheet transplantation [17].…”

Section: Introductionmentioning

confidence: 99%

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Establishment of a Rapid, Lesion-Controllable Retinal Degeneration Model in Monkey for Preclinical Stem Cell Therapy

Gao

Liu

et al. 2020

Preprint

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Background: Retinal degenerative disorders (RDs) are the main cause of blindness without curable treatment. Our previous studies have demonstrated that human induced pluripotent stem cells can differentiate into retinal organoids with all subtypes of retina, which provides huge promises for treating these diseases. Before it can be turned into reality, RD animal models are required to evaluate the safety and efficacy of stem cell therapy, and to develop the surgical tools and procedures for cell transplantation in patients. This study is to develop a monkey model of RD with controllable of lesion sites which can be rapidly prepared, for the studies of preclinical stem cell therapy among other applications.Methods: Sodium nitroprusside (SNP) in three doses was delivered into the monkey eye by subretinal injection (SI) and normal saline was applied as control. Structural and functional changes of the retinas were evaluated via multimodal imaging techniques and multifocal electroretinography (mfERG) before and after the treatment. Histological examination was performed to identify the target layer of the affected retina. The health status of monkeys was monitored during the experiment. Results: Well defined lesion with various degree of retinal degeneration was established at the posterior pole of retina as early as 7 days after SNP SI. The damage effect of SNP was dose-dependent. 0.05 mM SNP caused invisible structural changes in retina, similar to the control. 0.1 mM SNP led to the loss of outer retinal layer, including OPL, ONL and RPE, while 0.2 mM SNP impacted the entire layer of retina and choroid. MfERG showed reduced amplitude in the damaged region. The structural and functional damages were not recovered after 7-month follow-up. Conclusion: A simple, rapidly induced, lesion site-controllable, retinal degeneration model in monkey was established by the subretinal injection of 0.1 mM SNP. This monkey model closely mimics the histological changes of RDs, and provides a valuable platform for preclinical assessment of stem cell therapy.

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Photoreceptor degeneration by intravitreal injection of N-methyl-N-nitrosourea (MNU) in rabbits: a pilot study

Abstract: In rabbits, the intravitreal injection of 3 mg/kg BW MNU leads to selective but inhomogeneous photoreceptor degeneration.

Cited by 18 publications

References 26 publications

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

Adeno-associated virus-mediated neuroglobin overexpression ameliorates the N-methyl-N-nitrosourea-induced retinal impairments: a novel therapeutic strategy against photoreceptor degeneration

Establishment of a Rapid, Lesion-Controllable Retinal Degeneration Model in Monkey for Preclinical Stem Cell Therapy

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