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  1. Article ; Online: Topical Application of Deglycating Enzymes as an Alternative Non-Invasive Treatment for Presbyopia.

    Delanghe, Joris R / Beeckman, Jeroen / Beerens, Koen / Himpe, Jonas / Bostan, Nezahat / Speeckaert, Marijn M / Notebaert, Margo / Huizing, Manon / Van Aken, Elisabeth

    International journal of molecular sciences

    2023  Volume 24, Issue 8

    Abstract: Presbyopia is an age-related vision disorder that is a global public health problem. Up to 85% of people aged ≥40 years develop presbyopia. In 2015, 1.8 billion people globally had presbyopia. Of those with significant near vision disabilities due to ... ...

    Abstract Presbyopia is an age-related vision disorder that is a global public health problem. Up to 85% of people aged ≥40 years develop presbyopia. In 2015, 1.8 billion people globally had presbyopia. Of those with significant near vision disabilities due to uncorrected presbyopia, 94% live in developing countries. Presbyopia is undercorrected in many countries, with reading glasses available for only 6-45% of patients living in developing countries. The high prevalence of uncorrected presbyopia in these parts of the world is due to the lack of adequate diagnosis and affordable treatment. The formation of advanced glycation end products (AGEs) is a non-enzymatic process known as the Maillard reaction. The accumulation of AGEs in the lens contributes to lens aging (leading to presbyopia and cataract formation). Non-enzymatic lens protein glycation induces the gradual accumulation of AGEs in aging lenses. AGE-reducing compounds may be effective at preventing and treating AGE-related processes. Fructosyl-amino acid oxidase (FAOD) is active on both fructosyl lysine and fructosyl valine. As the crosslinks encountered in presbyopia are mainly non-disulfide bridges, and based on the positive results of deglycating enzymes in cataracts (another disease caused by glycation of lens proteins), we studied the ex vivo effects of topical FAOD treatment on the power of human lenses as a new potential non-invasive treatment for presbyopia. This study demonstrated that topical FAOD treatment resulted in an increase in lens power, which is approximately equivalent to the correction obtained by most reading glasses. The best results were obtained for the newer lenses. Simultaneously, a decrease in lens opacity was observed, which improved lens quality. We also demonstrated that topical FAOD treatment results in a breakdown of AGEs, as evidenced by gel permeation chromatography and a marked reduction in autofluorescence. This study demonstrated the therapeutic potential of topical FAOD treatment in presbyopia.
    MeSH term(s) Humans ; Presbyopia/drug therapy ; Aging ; Cataract/drug therapy ; Lens, Crystalline ; Glycation End Products, Advanced
    Chemical Substances Glycation End Products, Advanced
    Language English
    Publishing date 2023-04-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24087343
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Fructosyl Amino Oxidase as a Therapeutic Enzyme in Age-Related Macular Degeneration.

    Delanghe, Joris R / Diana Di Mavungu, Jose / Beerens, Koen / Himpe, Jonas / Bostan, Nezahat / Speeckaert, Marijn M / Vrielinck, Henk / Vral, Anne / Van Den Broeke, Caroline / Huizing, Manon / Van Aken, Elisabeth

    International journal of molecular sciences

    2024  Volume 25, Issue 9

    Abstract: Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key ... ...

    Abstract Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence (
    MeSH term(s) Macular Degeneration/drug therapy ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Humans ; Glycation End Products, Advanced/metabolism ; Animals ; Swine ; Retina/metabolism ; Retina/drug effects ; Retina/pathology ; Amino Acid Oxidoreductases
    Chemical Substances Glycation End Products, Advanced ; amadoriase (EC 1.5.3.-) ; Amino Acid Oxidoreductases (EC 1.4.-)
    Language English
    Publishing date 2024-04-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25094779
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: ICG-mediated photodisruption of the inner limiting membrane enhances retinal drug delivery

    Peynshaert, Karen / Vanluchene, Helena / De Clerck, Kaat / Minnaert, An-Katrien / Verhoeven, Morgane / Gouspillou, Noémie / Bostan, Nezahat / Hisatomi, Toshio / Accou, Geraldine / Sauvage, Félix / Braeckmans, Kevin / De Smedt, Stefaan / Remaut, Katrien

    Journal of controlled release. 2022 Sept., v. 349

    2022  

    Abstract: Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where ... ...

    Abstract Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where obstruction of the therapeutics at the inner limiting membrane (ILM) represents the dominant bottleneck. In this proof-of-principle study, we explore an innovative light-based approach to locally ablate the ILM in a minimally invasive and highly controlled manner, thus making the ILM more permeable for therapeutics. More specifically, we demonstrate that pulsed laser irradiation of ILM-bound indocyanine green (ICG), a clinically applied ILM dye, results in the formation of vapor nanobubbles which can disrupt the bovine ILM as well as the extraordinary thick human ILM. We have observed that this photodisruption allows for highly successful retinal delivery of model nanoparticles which are otherwise blocked by the intact ILM. Strikingly, this treatment is furthermore able of enhancing the efficacy of mRNA-loaded lipid nanoparticles within the bovine retina by a factor of 5. In conclusion, this study provides evidence for a light-based approach to overcome the ILM which has the potential to improve the efficacy of all retinal therapies hampered by this delivery barrier.
    Keywords blindness ; cattle ; drugs ; dyes ; humans ; intravitreal injection ; irradiation ; lipids ; nanobubbles ; retina ; therapeutics ; vapors
    Language English
    Dates of publication 2022-09
    Size p. 315-326.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2022.07.002
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: ICG-mediated photodisruption of the inner limiting membrane enhances retinal drug delivery.

    Peynshaert, Karen / Vanluchene, Helena / De Clerck, Kaat / Minnaert, An-Katrien / Verhoeven, Morgane / Gouspillou, Noémie / Bostan, Nezahat / Hisatomi, Toshio / Accou, Geraldine / Sauvage, Félix / Braeckmans, Kevin / De Smedt, Stefaan / Remaut, Katrien

    Journal of controlled release : official journal of the Controlled Release Society

    2022  Volume 349, Page(s) 315–326

    Abstract: Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where ... ...

    Abstract Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where obstruction of the therapeutics at the inner limiting membrane (ILM) represents the dominant bottleneck. In this proof-of-principle study, we explore an innovative light-based approach to locally ablate the ILM in a minimally invasive and highly controlled manner, thus making the ILM more permeable for therapeutics. More specifically, we demonstrate that pulsed laser irradiation of ILM-bound indocyanine green (ICG), a clinically applied ILM dye, results in the formation of vapor nanobubbles which can disrupt the bovine ILM as well as the extraordinary thick human ILM. We have observed that this photodisruption allows for highly successful retinal delivery of model nanoparticles which are otherwise blocked by the intact ILM. Strikingly, this treatment is furthermore able of enhancing the efficacy of mRNA-loaded lipid nanoparticles within the bovine retina by a factor of 5. In conclusion, this study provides evidence for a light-based approach to overcome the ILM which has the potential to improve the efficacy of all retinal therapies hampered by this delivery barrier.
    MeSH term(s) Animals ; Basement Membrane/surgery ; Biological Products ; Cattle ; Coloring Agents ; Humans ; Indocyanine Green ; Liposomes ; Nanoparticles ; RNA, Messenger ; Retina
    Chemical Substances Biological Products ; Coloring Agents ; Lipid Nanoparticles ; Liposomes ; RNA, Messenger ; Indocyanine Green (IX6J1063HV)
    Language English
    Publishing date 2022-07-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2022.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A Potential Role for Fructosamine-3-Kinase in Cataract Treatment.

    De Bruyne, Sander / van Schie, Loes / Himpe, Jonas / De Somer, Filip / Everaert, Inge / Derave, Wim / Van den Broecke, Caroline / Huizing, Manon / Bostan, Nezahat / Speeckaert, Marijn / Callewaert, Nico / Van Aken, Elisabeth / Delanghe, Joris R

    International journal of molecular sciences

    2021  Volume 22, Issue 8

    Abstract: Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure ... ...

    Abstract Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNFα, and IFNγ using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts.
    MeSH term(s) Animals ; Cataract/diagnosis ; Cataract/drug therapy ; Cataract/etiology ; Cataract/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Activation ; Eye/drug effects ; Eye/metabolism ; Glycation End Products, Advanced/administration & dosage ; Horses ; Humans ; Immunohistochemistry ; Intravitreal Injections ; Lens, Crystalline/drug effects ; Lens, Crystalline/metabolism ; Mice ; Phosphotransferases (Alcohol Group Acceptor)/administration & dosage ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/pharmacology ; Phosphotransferases (Alcohol Group Acceptor)/therapeutic use
    Chemical Substances Glycation End Products, Advanced ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; fructosamine-3-kinase (EC 2.7.1.-)
    Language English
    Publishing date 2021-04-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22083841
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Evaluation of UVA Cytotoxicity for Human Endothelium in an Ex Vivo Corneal Cross-linking Experimental Setting.

    Mooren, Pepijn / Gobin, Laure / Bostan, Nezahat / Wouters, Kristien / Zakaria, Nadia / Mathysen, Danny G P / Koppen, Carina

    Journal of refractive surgery (Thorofare, N.J. : 1995)

    2016  Volume 32, Issue 1, Page(s) 41–46

    Abstract: Purpose: To evaluate endothelial cytotoxicity after exposure of human corneas to ultraviolet-A (UVA) (λ = 365 nm; 5.4 J/cm(2)) in an experimental ex vivo corneal cross-linking setting.: Methods: Sixteen pairs of human donor corneas were cut into two ... ...

    Abstract Purpose: To evaluate endothelial cytotoxicity after exposure of human corneas to ultraviolet-A (UVA) (λ = 365 nm; 5.4 J/cm(2)) in an experimental ex vivo corneal cross-linking setting.
    Methods: Sixteen pairs of human donor corneas were cut into two pieces. One piece of each cornea was treated with 0.025% riboflavin solution prior to UVA irradiation (5 minutes; 18 mW/cm(2)), whereas the other piece was not irradiated but treated with riboflavin (right eye) or preservation medium (left eye). By irradiating from the endothelial side, the UVA dosage applied to endothelial cells exceeded at least eight times the cytotoxic threshold established in animal models (0.65 J/cm(2)). Endothelial cell counts were performed by two independent investigators after storage (4 to 5 days at 31 °C) and staining (trypan blue, alizarin red). Normality (Q-Q plot; Shapiro-Wilk test) and equivalence (mixed-effects modeling with a 10% equivalence threshold) of the endothelial cell counts of the different groups were evaluated.
    Results: Equivalence of mean endothelial cell density between both groups was observed: 2,237 ± 208 cells/mm(2) in UVA-irradiated pieces and 2,290 ± 281 cells/mm(2) in control pieces (mean difference of 53 ± 240 cells/mm(2) between both groups).
    Conclusions: Despite direct irradiation of human donor endothelium using the clinical dosage for cross-linking, equivalence in endothelial cell counts was observed between irradiated tissues and controls. Ex vivo human corneal endothelial cells seem to be far more resistant to riboflavin-enhanced UVA irradiation than previously estimated by animal experiments.
    MeSH term(s) Adult ; Aged ; Cell Count ; Collagen/metabolism ; Corneal Endothelial Cell Loss/physiopathology ; Corneal Stroma/metabolism ; Cross-Linking Reagents ; Endothelium, Corneal/pathology ; Endothelium, Corneal/radiation effects ; Eye Banks ; Humans ; Middle Aged ; Photochemotherapy ; Photosensitizing Agents/therapeutic use ; Radiation Injuries/physiopathology ; Riboflavin/therapeutic use ; Tissue Donors ; Ultraviolet Rays/adverse effects
    Chemical Substances Cross-Linking Reagents ; Photosensitizing Agents ; Collagen (9007-34-5) ; Riboflavin (TLM2976OFR)
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Journal Article
    ISSN 1081-597X
    ISSN 1081-597X
    DOI 10.3928/1081597X-20151207-05
    Database MEDical Literature Analysis and Retrieval System OnLINE

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