Review and Perspectives on Pharmacological Vitreolysis

Bandello, Francesco; Spina, Carlo La; Iuliano, Lorenzo; Fogliato, Giovanni; Parodi, Maurizio Battaglia

doi:10.1159/000354547

Cited by 8 publications

(8 citation statements)

References 58 publications

(58 reference statements)

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“…Among the non-enzymatic agents used for this purpose, RGD tripeptide was reported to be useful mainly as an interfactant to disrupt vitreoretinal adhesion 35 . However, the study had some limitations and there has been no further progress in the area of RGD-assisted PVD 9,10 .…”

Section: Discussionmentioning

confidence: 99%

“…to facilitate the induction of PVD. The pharmacological reagents thus far attempted for vitreolysis are enzymatic (such as bacterial collagenase, hyaluorinidase, dispase, plasmin and ocriplasmin) or non-enzymatic (such as vitreosolve and RGD based peptides) 9 . Of the several enzymatic reagents, the plasmin-derived ocriplasmin has been the only reagent approved by the FDA.…”

mentioning

confidence: 99%

“…Non-enzymatic reagents developed to achieve vitrectomy offer the added benefit of safety without any collateral damage to the retinal structures. In this direction, the RGD (Arg-Gly-Asp) containing peptides have been used to induce PVD 9,10 .…”

mentioning

confidence: 99%

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Induction of posterior vitreous detachment (PVD) by non-enzymatic reagents targeting vitreous collagen liquefaction as well as vitreoretinal adhesion

Santra

Sharma

Katoch

et al. 2020

Sci Rep

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induction of posterior vitreous detachment (pVD) by pharmacologic vitreolysis has been largely attempted through the use of enzymatic reagents. ocriplasmin has been the only fDA-approved clinical reagent so far. Several adverse effects of ocriplasmin have emerged, however, and the search for alternative pVD-inducing reagents continues. Since i) collagen forms an important structural component of the vitreous, and ii) strong vitreo-retinal adhesions exist between the cortical vitreous and the internal limiting membrane (ILM) of the retina, an effective PVD-inducing reagent would require both, vitreous liquefaction, and concurrent dehiscence of vitreoretinal adhesion, without being toxic to retinal cells. We designed a combination of two reagents to achieve these two objectives; a triple helix-destabilizing collagen binding domain (cBD), and a fusion of RGD (integrin-binding) tripeptide with cBD (RcBD) to facilitate separation of posterior cortical vitreous from retinal surface. Based on in vitro, ex-vivo, and in vivo experiments, we show that a combination of cBD and RcBD displays potential for safe pharmacologic vitreolysis. Our findings assume significance in light of the fact that synthetic RGD-containing peptides have already been used for inhibition of tumor cell invasion. proteins such as variants of collagen binding domains could have extended therapeutic uses in the future. The vitreous humor is a hydrogel present in the eye; an intact vitreous gel is important for ocular health. However, with aging, the gel undergoes a gradual, spontaneous process of liquefaction, and separates from the retina, resulting in posterior vitreous detachment or PVD 1-3. Therefore, it is not surprising that there is a high incidence of vitreo-retinal disorders in later decades of life, with the peak of incidence of retinal conditions matching the peak age of incidence of posterior vitreous separation 4-6. When the gel liquefaction exceeds the extent of vitreo-retinal dehiscence, anomalous PVD occurs, which is characterized by partial or incomplete detachment of vitreous from the retina. Anomalous PVD can involve exertion of excessive tractional forces acting upon the retina, which can lead to many ophthalmic complications such as hemorrhage, retinal tears, or detachment, macular hole formation, and vitreomacular traction syndrome 3,7,8. The mainstream treatment of incomplete PVD is surgical intervention or vitrectomy, to create a clean retinal surface devoid of any vitreous remnants and thus avoid further complications such as proliferative vitreoretinopathy (PVR). However, owing to its invasive nature and associated risks, surgical vitrectomy is not an ideal choice, except in cases complicated by retinal detachments. In paediatric patients, induction of posterior vitreous detachment (PVD) is an important and challenging step in the successful management of retinal detachment or traumatic macular hole, owing to the firm vitreoretinal adhesions. Pharmacological vitrectomy has been explored as a non-surgical, safer and cleaner al...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of posterior vitreous detachment (PVD) by non-enzymatic reagents targeting vitreous collagen liquefaction as well as vitreoretinal adhesion

Santra

Sharma

Katoch

et al. 2020

Sci Rep

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“…Proteolytic activities can cause photoreceptor damage, which may result in visual impairment in more serious cases [18][19][20]. Moreover, the autolytic degradation of ocriplasmin causes its fast inactivation after vitreous injection [21,22].…”

mentioning

confidence: 99%

Mutational Analysis of Ocriplasmin to Reduce Proteolytic and Autolytic Activity in Pichia Pastoris

Baghban

Farajnia

Ghasemi

et al. 2020

Preprint

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Background: Ocriplasmin (Jetrea) is using for the treatment of symptomatic vitreomacular adhesion. This enzyme undergoes rapid inactivation and limited activities duration as a result of its autolytic and proteolytic nature after injection within the eye. Moreover, the proteolytic activities can cause photoreceptor damage, which may result in visual impairment in the more serious cases.Results: The present research aimed to reduce the disadvantages of ocriplasmin using site-directed mutagenesis. To reduce the autolytic activity of ocriplasmin in the first variant, lysine 156 changed to glutamic acid and in the second variant for the proteolytic activity reduction, alanine 59 mutated to threonine. The third variant contained both the mutations. Expression of wild type and three mutant variants of ocriplasmin constructs were done in Pichia pastoris expression system. The mutant variants analyzed in silico and in vitro and compared to the wild type. The kinetic parameters of ocriplasmin variants showed both variants with K156E substitution were more resistant to autolytic degradation than wild-type. These variants also exhibited reduced Kcat and Vmax values. An increase in their Km values, leading to a decreased catalytic efficiency (the Kcat/Km ratio) of autolytic and mix variants. Moreover, in variant with A59T mutation, Kcat and Vmax values have reduced compared to wild type. The mix variants showed the most increase in Km value (almost 2-fold) as well as reduced enzymatic affinity to the substrate. Thus, the results indicated combine mutations at ocriplasmin sequence were more effective compared with single mutations. Conclusions: The results indicated such variants represent valuable tools for the investigation of therapeutic strategies aiming at non-surgical resolution of vitreomacular adhesion.

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“…И плазмин, и его активаторы нашли свое применение в офтальмологии, однако в связи со сложностью дозирования и рядом побочных эффектов применения плазмина именно его активаторы приобрели большее значение [2].…”

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Effects of urokinase plasminogen activator on cultured human retinal epithelial cells

2017

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Review and Perspectives on Pharmacological Vitreolysis

Cited by 8 publications

References 58 publications

Induction of posterior vitreous detachment (PVD) by non-enzymatic reagents targeting vitreous collagen liquefaction as well as vitreoretinal adhesion

Induction of posterior vitreous detachment (PVD) by non-enzymatic reagents targeting vitreous collagen liquefaction as well as vitreoretinal adhesion

Mutational Analysis of Ocriplasmin to Reduce Proteolytic and Autolytic Activity in Pichia Pastoris

Effects of urokinase plasminogen activator on cultured human retinal epithelial cells

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