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Title: Modulation of conjunctival scarring following glaucoma filtration surgery
Author: Dhingra, S.
ISNI:       0000 0004 8497 6392
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Conjunctival scarring is the main cause of failure following glaucoma filtration surgery (GFS). Anti-metabolites used clinically to prevent scarring improve outcomes in only some patients and are associated with potentially blinding adverse effects. Thus, novel anti-scarring agents are needed. The hypothesis underlying this thesis was that prolonged local administration of an antiscarring agent to the sub-conjunctiva would reduce scarring after GFS. Two novel candidates were assessed using a multi-disciplinary approach: matrix metalloproteinase (MMP) inhibitors and serum amyloid P (SAP). MMPs are enzymes responsible for extracellular matrix remodelling that may contribute to scarring. To avoid the need for multiple injections into the subconjunctival bleb, MMP inhibitor implants were developed for use in a rabbit model of GFS. Anterior chamber slit lamp optical coherence tomography revealed that an ilomastat implant failed to dissolve over a 30-day period following GFS, and histology demonstrated an adverse foreign body reaction. Two MMP inhibitors with higher solubilities were assessed as alternatives to ilomastat. Of these, AZ 6357 was found to dissolve rapidly, inhibit fibroblastmediated collagen contraction, have minimal toxicity against fibroblasts in vitro and to dissolve within 7 days to prolong bleb survival in vivo (rabbit GFS model). Microarray gene expression studies revealed that interleukin-1 and other pro-inflammatory mediators were up-regulated following GFS, as were MMP-1, -3, -9 (borderline result), -12 and -13. SAP inhibits transformation of fibrocytes to fibroblasts, the transformation being an important event in scarring. Intra-bleb injections of two doses of human recombinant SAP, PRM-151, were found to prolong bleb survival with no obvious signs of toxicity in the rabbit GFS model. Drug precipitation occurred on injection, indicating the requirement for an improved formulation. These data indicate that inhibition of MMPs (with the AZ 6357 implant) and/or transformation of fibroblasts to fibrocytes (with PRM-151) are promising approaches to anti-scarring therapy for use in GFS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available