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Title: Investigating small molecule therapeutics to improve regeneration and functional recovery following peripheral nerve damage
Author: Rayner, Melissa Lucy Doreen
ISNI:       0000 0004 7964 9020
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Peripheral nerve injury (PNI) can be debilitating and results in loss of function, coupled with slow neuron regeneration. Microsurgical treatments remain the gold standard therapy, with no drug therapies currently available. Effective pharmacological treatments could potentially maintain neuronal viability, encourage axonal growth, improve axonal specificity to targets and reduce neuropathic pain. Some drugs and targets have been identified but challenges remain with clinical translation. Advancements in understanding the molecular and cellular events occurring following PNI identifies signalling pathways that could be targeted with drug therapies. The failure in drug therapies reaching PNI clinical trials may be due to the lack of effective in vitro and in vivo pre-clinical models. This study developed and applied models to be used as effective screening tools to address this need. Many compounds demonstrated positive effects on neurite growth when screened in a 3D-engineered co-culture model. NSAIDs (ibuprofen and sulindac sulfide) demonstrated beneficial effects and were studied further in two injury models demonstrating increased axonal growth and improved function. Local controlled-release drug delivery systems have become more attractive because of the drawbacks in conventional drug treatments. This study investigated drug release from various biomaterials in order to obtain an optimal material for implantation and sustained drug delivery. Suitable biomaterials were implanted in vivo to deliver ibuprofen or sulindac sulfide. Both drugs demonstrated beneficial effects on axonal regeneration and functional recovery. Embedding drugs into biocompatible and bio-degradable materials provides effective delivery systems for future translation. Studying NSAIDs revealed a previously unreported relationship between PPAR-γ affinity and regeneration. A NSAID derivative demonstrated the greatest effects on neurite growth in vitro at lower doses than other compounds tested. In summary, this work has identified therapeutic targets to aid the development of novel compounds, as well as, drug repurposing, and effective tools for the pre-clinical screening of these drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available