Non-viral gene therapy to prevent cartilage degeneration in Osteoarthritis
Dr C Curtain
Dr O Kennedy
Dr F O'Brien
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Osteoarthritis (OA) is the most common form of joint disease, affecting one in five people in the EU and results in activity limitations for approximately one in ten. There is no treatment to reverse or prevent the progression of OA, with the two primary options being pain management, or ultimately total joint replacement. For pain management, intra-articular (IA) steroid injections are regularly used to postpone joint replacement. Crucially steroid injections reduce inflammation, and thus pain, but do not actually target or alter the behaviour of cells or tissues within the joint and have recently been reported to actually increase cartilage loss. Therefore, there is a major unmet clinical need for novel disease modifying therapeutics proposed in this application.
This project will explore the potential for controlled delivery of novel genetic cargos using non-viral vectors to augment and improve the existing practice of IA steroid delivery. This will allow us to target the cause, as well as the painful symptoms, of the OA disease process. We have vast experience using non-viral gene delivery methods (with vectors such as polyethyleneimine (PEI) and chitosan) to modulate cell behaviour. More recently, we have optimised a novel GAG-binding enhanced transduction system (peptide (GET system; developed by our collaborator, Dr. James Dixon, University of Nottingham). In this system a multi-domain protein glycosaminoglycan (GAG)-binding capability will be tested in terms of its ability to deliver pDNA, miRNA and siRNA to modulate, and re-balance, anabolic/catabolic activities of chondrocyte cells in OA (using cell culture and explantmodels). In parallel, human mesenchymal stem cells (MSCs) will also be targeted for transfection with therapeutic pDNA, miRNA and siRNA.
These will also be included in OA model systems to determine their ability to modulate OA progression. Therapeutic strategies based on miRNA/siRNA technology are extremely appealing as, unlike protein inhibitors or pDNA delivery (which only targets one protein at a time) - they can intercept entire gene cohorts. This multi-targeting effect on protein expression can modulate several cellular processes, thus makes miRNA/siRNA-based therapeutics particularly valuable and promising.
The specific aims of this project are:
(1) To develop therapeutic gene delivery techniques to articular chondrocytes and MSCs using cell culture systems
(2) Functionalise and optimise gene delivery vectors to in situ chondrocytes using explants models of OA (using targeted antibodies and biomaterials)
(3) Test therapeutic efficacy in vivo, using a pre-clinical rodent model of OA
The impact of this research will be to establish optimal gene delivery techniques for modulating the disease process in OA. These will be developed in 2D cell culture systems (chondrocytes, MSCs), 3D explant models and finally tested in a pre-clinical model of OA. The technology proposed here would have the potential to alleviate suffering and enable sustained healthcare benefits for the aging worldwide population.