scholarly journals Nano-enhanced optical gene delivery to retinal degenerated mice

2019 ◽  
Author(s):  
Subrata Batabyal ◽  
Sivakumar Gajjeraman ◽  
Sulagna Bhattacharya ◽  
Weldon Wright ◽  
Samarendra Mohanty
Keyword(s):  
Gene Delivery ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Continuous Wave ◽  
Inflammatory Responses ◽  
Field Enhancement ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Low Efficiency

ABSTRACTThe efficient and targeted delivery of genes and other impermeable therapeutic molecules into retinal cells is of immense importance for therapy of various visual disorders. Traditional methods for gene delivery require viral transfection, or chemical methods that suffer from one or many drawbacks such as invasiveness, low efficiency, lack of spatially targeted delivery, and can generally have deleterious effects such as unexpected inflammatory responses and immunological reactions. Here, we introduce a continuous wave near-infrared laser-based Nano-enhanced Optical Delivery (NOD) method for spatially controlled delivery of opsin-encoding genes into retina in-vivo. In this method, the optical field enhancement by gold nanorods is utilized to transiently permeabilize cell membrane enabling delivery of exogenous impermeable molecules to nanorod-binding cells in laser-irradiated regions. The successful delivery and expression of opsin in targeted retina after in-vivo NOD in the mice models of retinal degeneration opens new vista for re-photosensitizing retina with geographic atrophies as in dry age-related macular degeneration (AMD).

scholarly journals Nano-enhanced Optical Gene Delivery to Retinal Degenerated Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 318-329 ◽  
Author(s):  
Subrata Batabyal ◽  
Sivakumar Gajjeraman ◽  
Sulagna Bhattacharya ◽  
Weldon Wright ◽  
Samarendra Mohanty
Keyword(s):  
Gene Delivery ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Structural Integrity ◽  
Continuous Wave ◽  
Inflammatory Responses ◽  
Age Related Macular Degeneration ◽  
Cellular Expression ◽  
Age Related

Background: The efficient and targeted delivery of genes and other impermeable therapeutic molecules into retinal cells is of immense importance for the therapy of various visual disorders. Traditional methods for gene delivery require viral transfection, or chemical methods that suffer from one or many drawbacks, such as low efficiency, lack of spatially targeted delivery, and can generally have deleterious effects, such as unexpected inflammatory responses and immunological reactions. Methods: We aim to develop a continuous wave near-infrared laser-based Nano-enhanced Optical Delivery (NOD) method for spatially controlled delivery of ambient-light-activatable Muti-Characteristic opsin-encoding genes into retina in-vivo and ex-vivo. In this method, the optical field enhancement by gold nanorods is utilized to transiently permeabilize cell membrane, enabling delivery of exogenous impermeable molecules to nanorod-binding cells in laser-irradiated regions. Results and Discussion: With viral or other non-viral (e.g. electroporation, lipofection) methods, gene is delivered everywhere, causing uncontrolled expression over the whole retina. This will cause complications in the functioning of non-degenerated areas of the retina. In the NOD method, the contrast in temperature rise in laser-irradiated nanorod-attached cells at nano-hotspots is significant enough to allow site-specific delivery of large genes. The in-vitro and in-vivo results using NOD, clearly demonstrate in-vivo gene delivery and functional cellular expression in targeted retinal regions without compromising the structural integrity of the eye or causing immune response. Conclusion: The successful delivery and expression of MCO in the targeted retina after in-vivo NOD in the mice models of retinal degeneration opens a new vista for re-photosensitizing retina with geographic atrophies, such as in dry age-related macular degeneration.

scholarly journals Anti-inflammatory Effects of GTE in Eye Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Jian Li ◽  
Lin Du ◽  
Jing Na He ◽  
Kai On Chu ◽  
Cosmos Liutao Guo ◽  
...  
Keyword(s):  
Green Tea ◽  
Inflammatory Responses ◽  
Ocular Inflammation ◽  
Eye Diseases ◽  
Biologically Active ◽  
Age Related Macular Degeneration ◽  
Experimental Investigations ◽  
Age Related

Ocular inflammation is a common complication of various eye diseases with wide consequences from irritations to potentially sight-threatening complications. Green tea is a popular beverage throughout the world. One of the proven health benefits of consuming green tea extract (GTE) is anti-inflammation. Catechins are the biologically active constituents of GTE. In in vitro and in vivo studies, GTE and catechins present inhibition of inflammatory responses in the development of ocular inflammation including infectious, non-infectious or autoimmune, and oxidative-induced complications. Research on the ocular inflammation in animal models has made significant progress in the past decades and several key disease mechanisms have been identified. Here we review the experimental investigations on the effects of GTE and catechins on various ocular inflammation related diseases including glaucoma, age-related macular degeneration, uveitis and ocular surface inflammation. We also review the pharmacokinetics of GTE constituents and safety of green tea consumption. We discuss the insights and perspectives of these experimental results, which would be useful for future development of novel therapeutics in human.

Nanotherapies for the Treatment of Age-Related Macular Degeneration (AMD) Disease: Recent Advancements and Challenges

2020 ◽  
Vol 13 (4) ◽  
pp. 283-290 ◽  
Author(s):  
Vamshi Krishna Rapalli ◽  
Srividya Gorantla ◽  
Tejashree Waghule ◽  
Arisha Mahmood ◽  
Prem Prakash Singh ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Targeted Delivery ◽  
Large Population ◽  
Posterior Part ◽  
Therapeutic Agents ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Disease Site ◽  
Therapeutic Molecules ◽  
Invasive Techniques

Age-related Macular Degeneration (AMD) is one of the common diseases affecting the posterior part of the eye, of a large population above 45 years old. Anti-Vascular Endothelial Growth Factor- A (Anti-VEGF-A) agents have been considered and approved as therapeutic agents for the treatment of AMD. Due to the large molecular weight and poor permeability through various eye membranes, VEGF-A inhibitors are given through an intravitreal injection, even though the delivery of small therapeutic molecules by topical application to the posterior part of the eye exhibits challenges in the treatment. To overcome these limitations, nanocarrier based delivery systems have been utilized to a large extent for the delivery of therapeutics. Nanocarriers system offers prodigious benefits for the delivery of therapeutics to the posterior part of the eye in both invasive and non-invasive techniques. The nano size can improve the permeation of therapeutic agent across the biological membranes. They provide protection from enzymes present at the site, targeted delivery or binding with the disease site and extend the release of therapeutic agents with prolonged retention. This leads to improved therapeutic efficacy, patient compliance, and cost effectiveness of therapy with minimum dose associated side-effects. This review has summarized various nanocarriers explored for the treatment of AMD and challenges in translation.

scholarly journals Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donita L. Garland ◽  
Eric A. Pierce ◽  
Rosario Fernandez-Godino
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Deposit Formation ◽  
Genetic Ablation ◽  
Age Related ◽  
Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

scholarly journals The anti-angiogenic isoforms of VEGF in health and disease

2009 ◽  
Vol 37 (6) ◽  
pp. 1207-1213 ◽  
Author(s):  
Yan Qiu ◽  
Coralie Hoareau-Aveilla ◽  
Sebastian Oltean ◽  
Steven J. Harper ◽  
David O. Bates
Keyword(s):  
Splice Site ◽  
Site Selection ◽  
Age Related Macular Degeneration ◽  
Splicing Factor ◽  
Splice Site Selection ◽  
Age Related ◽  
Normal Human ◽  
Radical Revision

Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys–Drash syndrome and pre-eclampsia). Administration of recombinant VEGF165b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGFxxxb isoforms to the pro-angiogenic VEGFxxx isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGFxxxb isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.

scholarly journals Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽  
2021 ◽  
Author(s):  
Anna K. Dreismann ◽  
Michelle E. McClements ◽  
Alun R. Barnard ◽  
Elise Orhan ◽  
Jane P. Hughes ◽  
...  
Keyword(s):  
Complement System ◽  
Functional Expression ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related ◽  
The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).

scholarly journals Functional optical coherence tomography of retinal photoreceptors

2018 ◽  
Vol 243 (17-18) ◽  
pp. 1256-1264 ◽  
Author(s):  
Xincheng Yao ◽  
Taeyoon Son ◽  
Tae-Hoon Kim ◽  
Yiming Lu
Keyword(s):  
Vision Loss ◽  
Objective Assessment ◽  
Age Related Macular Degeneration ◽  
Retinal Stimulation ◽  
Age Related ◽  
Retinal Photoreceptors ◽  
Severe Vision Loss ◽  
Further Development

Age-related macular degeneration (AMD) is the leading cause of severe vision loss and legal blindness. It is known that retinal photoreceptors are the primary target of AMD. Therefore, a reliable method for objective assessment of photoreceptor function is needed for early detection and reliable treatment evaluation of AMD and other eye diseases such as retinitis pigmentosa that are known to cause photoreceptor dysfunctions. Stimulus-evoked intrinsic optical signal (IOS) changes promise a unique opportunity for objective assessment of physiological function of retinal photoreceptor and inner neurons. Instead of a comprehensive review, this mini-review is to provide a brief summary of our recent in vitro and in vivo optical coherence tomography (OCT) studies of stimulus-evoked IOS changes in animal retinas. By providing excellent axial resolution to differentiate individual retinal layers, depth-resolved OCT revealed rapid IOS response at the photoreceptor outer segment. The fast photoreceptor-IOS occurred almost right away (∼ 2 ms) after the onset of retinal stimulation, differentiating itself from slow IOS changes correlated with inner neural and hemodynamic changes. Further development of the functional IOS instruments and retinal stimulation protocols may provide a feasible solution to pursue clinical application of functional IOS imaging for objective assessment of human photoreceptors. Impact statement Retinal photoreceptors are the primary target of age-related macular degeneration (AMD) which is the leading cause of severe vision loss and legal blindness. An objective method for functional assessment of photoreceptor physiology can benefit early detection and better treatment evaluation of AMD and other eye diseases that are known to cause photoreceptor dysfunctions. This article summarizes in vitro study of IOS mechanisms and in vivo demonstration of IOS imaging of intact animals. Further development of the functional IOS imaging may provide a revolutionary solution to achieve objective assessment of human photoreceptors.

scholarly journals Niobium Carbide Loaded by Macrophage for Targeted Phototherapy Ablation of Breast Cancer

2020 ◽  
Author(s):  
Chiara Da Pieve ◽  
Gabriela Kramer Marek ◽  
Jolanta Saczko ◽  
Anant Shah ◽  
Florian Raes
Keyword(s):  
Animal Study ◽  
Human Body ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Niobium Carbide ◽  
Reactive Oxygen Species Generation ◽  
Large Animal Model ◽  
Large Animal ◽  
Photodynamic Effect

ABSTRACTAltough nanomaterial-mediated phototherapy has been extensively studied, the major antitumor success is limited to treating subcutaneous tumor on nude, lacking of clinically-relevant big animal study. Therefore, it is urgent to make further investigation on the typical big model, which is more closely related to the human body. In this work, niobium carbide (NbC) was selected as photoactive substance in virtue of its outstanding near infrared (NIR) absorption properties and resultantly NIR-triggered hyperthemia and reactive oxygen species generation for the synergetic photothermal and photodynamic effect. Moreover, macrophage was used as bio-carrier for the targeted delivery of NbC and the phagocytosis of macrophages was proved to be able to retain the photothermal/photodynamic effect of NbC. Resultantly, macrophage loaded NbC could realize complete removal of solid tumor on both of nude mice and big animal of rabbits. Meanwhile, two-dimensional ultrasound, shave wave elastography (SWE) and contrast-enhanced ultrasound (CEUS) have been applied for monitoring the physiological evolutions of in vivo tumor post treatment, which clearly disclosed the photoablation process of tumor and provided a new way for the surveillance of tumor on the big animal study. Hence, large animal model study in this work presented higher clinical significance than the previous studies.SignificanceFindings show that niobium carbide carried by macrophages can be used for targeted phototherapy. At the same time, we applied the rabbit tumor model which is closer to the human body microenvironment.

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