Programme Leader: Prof Martin Bachmann, Jenner Institute, University of Oxford
Pain is one of the great unmet clinical needs
The majority of patients with chronic pain can't find effective treatments. Long-term usage of available strong opiate based medicines (prescribed as a last resort) causes serious side-effects. In particular, persistent pain in inflammatory conditions such as rheumatoid arthritis and degenerative arthritis (osteoarthritis) is amongst the most challenging of symptoms, contributing to the restriction of mobility and overall fatigue in affected individuals.
BackgroundChronic pain results from increased nociceptive signalling
Inflammation in arthritis increases the production of a chemical messenger called nerve growth factor (NGF). These molecules activate special nerve cells responsible for relaying pain messages to the central nervous system, resulting in hypersensitivity to various stimuli and contributing to persistent pain.
Biologics (drugs that mimic immune molecules called antibodies) that selectively target and block NGF’s action, have demonstrated significant pain-relief in animal models and human clinical trials. Indeed, the evaluation of anti-NGF antibody drugs are at an advanced stage, both validating the concept and revealing clues as to potential clinical applications for arthritis.
A vaccine that teaches the body’s immune system to produce NGF antibodies could offer lasting pain-relief with improved affordability. In addition, research to investigate the pain signalling mechanisms affected by such therapies may provide insight into their role in musculoskeletal inflammatory conditions such as arthritis. By replacing frequent injections of biologic drugs with less frequent, small volume (much lower dose) vaccine jabs, treatment is simplified. The cost implications of lower doses could also make this therapy more widely available and an attractive option for individuals and health professionals alike.
Our research, supported by the charity Versus Arthritis, will help evaluate the merits of this vaccine based approach and lay the foundations for related studies that may help in exploring the role that pain molecules play in disease progression.
Nerve growth factor (NGF) has been identified as a major mediator of chronic pain and a potential therapeutic target to provide relief from arthritic pain refractory to alternative treatments. © M. Mohsen, University of Bern
- We will design and produce vaccine candidates in the laboratory which are compatible with industrial manufacturing methods.
- We will test if these vaccines work by injecting laboratory mice. (a) Blood analysis will assess anti-NGF antibody levels generated, examining their activity in detail. (b) Optimal candidate(s) will be used to alleviate pain in a well-established pain mouse model.
- Using NGF reactive cells derived from cell lines and/ or arthritis patients we will test if vaccines can block NGF- mediated pain signalling.
Anti-NGF vaccine based on VLP can induce good levels of anti-NGF IgG antibodies, and these were able to demonstrate the ability to block the NGF-mediated biological actions on NGF reactive cells in vitro. This cell model uses the same signalling receptors as involved in pain signalling.
Neuron-like cells remain rounded without NGF (left), the addition of NGF and it's interaction with its receptor at the cell surface leads to differentiation and stimulates thin projections (called neurite outgrowth) proportional to the amount of NGF (middle), the addition of vaccine-induced antibodies reduces the numbers of cells showing neurites (right) showing the potential to reduce pain signalling.
Further research continues to investigate ways to improve the stability and efficacy of the vaccine. Additional versions are also being developed for companion animals. Clinical evaluation will look to determine the safety and efficacy of this active immunisation approach in targeting NGF.