Peptide-based matrix gene delivery for tissue regeneration and anti-microbial therapy targeting periodontal disease

Project description

Project Summary

Periodontitis is the sixth most prevalent disease in the world, mostly (but not exclusively) affecting adults in their thirties and forties with a peak incidence at around 38 years of age 1. Periodontitis is a polymicrobial infection caused by co-operating consortia of organisms, predominantly growing as biofilms2. Periodontal pockets may harbour up to 108 diverse bacteria 3. The same bacteria are also associated with systemic effects through gaining access to the blood and the chronic infection/inflammation associated with periodontitis can underlie pathology at non-oral sites. P. gingivalis, a key periodontal pathogen, has been shown to invade human aortic endothelial cells and induced the production of pro-inflammatory molecules. It has been recovered from distant sites including atherosclerotic plaques, inflamed joints and brain tissue 4,5 Chronic periodontitis, advanced inflammatory periodontal disease, is a major cause of tooth loss significantly affecting the quality of life of patients with diverse chronic disease backgrounds. Current clinical treatment strategies, conservative and surgical, lack solutions effectively offering simultaneous and sustained periodontal tissue regeneration and anti-microbial action6. This relevant high-impact oral health challenge affecting up to 1/3rd of the population therefore requires advanced multi-modal treatment strategies to effectively combat infection, inflammation whilst supporting tissue regeneration.

Self-assembly peptides (SAPs) are self-assembling injectable molecules that can respond to environmental triggers forming a biomimetic hydrogel scaffold, with multiple capabilities to support enamel regeneration and mineralisation9,10. Rational design and optimisation of these system could potentially deliver a wide range of additional therapeutics depending on sequence, concentration, charge and hierarchical structures present. The properties of the hydrogel can be tailored to specific oral environments. Incorporating advanced drug payloads such as non-viral gene therapeutics into injectable SAP biomaterials could cost-effectively offer the potential to provide targeted advanced regenerative cues and anti-microbial action by delivering growth factor and antimicrobial genes directly to target cells at the defect whilst simultaneously providing a regenerative matrix. Such an approach would therefore minimally invasively address significant clinical challenges in dental and musculoskeletal research.

The present project is aimed at developing SAP-gene therapeutic combination treatments through peptide-chemistry, biomaterial sciences as well as molecular and cell biological approaches in vitro. The project has the potential to generate new intellectual property, preclinical research data and facilitates interdisciplinary collaboration. SAP-gene therapeutics will be optimised and characterised with regard to the physico-chemical properties of the peptide sequence and release studies will be investigated via a number of analytical techniques (HPLC MS/ UV and FTIR spectroscopy). Biocompatibility and gene delivery efficacy testing in cell culture will be performed using clinically relevant mesenchymal dental pulp stem cells (DPSCs) extracted from teeth. Furthermore, a novel strategy incorporating functional groups for cross-linking therapeutic DNA with SAPs to improve payload delivery will be investigated.

Successively to delivery optimisation, this project will investigate osteoinductive, angiogenic and antimicrobial candidate genes and gene-activated matrix systems in 3D DPSC cultures to identify most promising delivery strategies for subsequent translation-geared preclinical development.

Entry requirements

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+44 (0)113 343 7497