Successful Subretinal Delivery and Monitoring of MicroBeads in Mice

Fischer, Manuel; Goldmann, Tobias; Wallrapp, Christine; Mühlfriedel, Regine; Beck, Susanne; Stern-Schneider, Gabi; Ueffing, Marius; Wolfrum, Uwe; Seeliger, Mathias W.

doi:10.1371/journal.pone.0055173

Cited by 12 publications

(14 citation statements)

References 33 publications

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“…In pre-clinical settings, ab externo SR injection has been successfully tested in mice (Fischer et al, 2013), rabbits (Peden et al, 2011; Martorana et al, 2012), and pigs (Smet et al, 2012). The procedure involves penetration of the conjunctiva, sclera, choroid, and RPE at the equatorial region in order to reach the subretinal space without disrupting the retina.…”

Section: Subretinal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

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An exceptionally high number of monogenic disorders lead to incurable blindness, making them targets for the development of gene-therapy. In order to successfully apply therapeutic vector systems in vivo, the heterogeneity of the disease phenotype needs to be considered. This necessitates tailored approaches such as subretinal or intravitreal injections with the aim to maximize transduction of target cell populations, while minimizing off-target effects and surgical complications. Strategic decisions on parameters of the application are crucial to obtain the best treatment outcomes and patient safety. While most of the current retinal gene therapy trials utilize a subretinal approach, a deeper understanding of the numerous factors and considerations in choosing one delivery approach over the other for various ocular pathologies could lead to an improved safety and treatment efficacy. In this review we survey different vector injection techniques and parameters applied in recent retinal (pre-)clinical trials. We explore the advantages and shortcomings of each delivery strategy in the setting of different underlying ocular pathologies and other relevant factors. We highlight the potential benefits for patient safety and efficacy in applying those considerations in the decision making process.

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Section: Subretinal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

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“…The miniaturized CellBeads for use in mice have a diameter of 154 ± 5 μm, each bead containing about 50–70 GFP-secreting cells. Injections were performed as previously reported [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Scale Adjustments to Facilitate Two-Dimensional Measurements in OCT Images

et al. 2015

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PurposeTo address the problem of unequal scales for the measurement of two-dimensional structures in OCT images, and demonstrate the use of intra¬ocular objects of known dimensions in the murine eye for the equal calibration of axes.MethodsThe first part of this work describes the mathematical foundation of major distortion effects introduced by X-Y scaling differences. Illustrations were generated with CorelGraph X3 software. The second part bases on image data obtained with a HRA2 Spectralis (Heidelberg Engineering) in SV129 wild-type mice. Subretinally and intravitreally implanted microbeads, alginate capsules with a diameter of 154±5 μm containing GFP-marked mesenchymal stem cells (CellBeads), were used as intraocular objects for calibration.ResultsThe problems encountered with two-dimensional measurements in cases of unequal scales are demonstrated and an estimation of the resulting errors is provided. Commonly, the Y axis is reliably calibrated using outside standards like histology or manufacturer data. We show here that intraocular objects like dimensionally stable spherical alginate capsules allow for a two-dimensional calibration of the acquired OCT raw images by establishing a relation between X and Y axis data. For our setup, a correction factor of about 3.3 was determined using both epiretinally and subretinally positioned beads (3.350 ± 0.104 and 3.324 ± 0.083, respectively).ConclusionsIn this work, we highlight the distortion-related problems in OCT image analysis induced by unequal X and Y scales. As an exemplary case, we provide data for a two-dimensional in vivo OCT image calibration in mice using intraocular alginate capsules. Our results demonstrate the need for a proper two-dimensional calibration of OCT data, and we believe that equal scaling will certainly improve the efficiency of OCT image analysis.

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“…This approach indicates the presence of cells that are metabolically active expressing the reporter gene [ 96 ]. Fischer and colleagues transfected human BM-MSCs with a plasmid expression vector encoding enhanced GFP (eGFP) and incorporated the cells into miniaturized alginate spheres (MicroBeads) [ 97 ]. Then, the MicroBeads were subretinally implanted and tracked using cSLO [ 97 ].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Bone Marrow‐Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

Mesentier-Louro

Zaverucha-do-Valle

Rosado-de-Castro

et al. 2015

Stem Cells International

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Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

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Successful Subretinal Delivery and Monitoring of MicroBeads in Mice

Cited by 12 publications

References 33 publications

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Scale Adjustments to Facilitate Two-Dimensional Measurements in OCT Images

Bone Marrow‐Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

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