The goal of my research is to develop NanoTherapy, especially in the fields of
(i) immunemediated disease and (ii) neurodegenerative disease. Working with Tarek Fahmy (Yale University) and Terry Strom (Harvard University), a nanotherapeutic device able to target leukaemia inhibitory factor (LIF) to specific cell types has been developed, enabling exploitation of our discovery that LIF opposes interleukin (IL)-6, and thus in turn opposes IL-6–driven pathologies. In my own lab, first recognition of LIF as a critical mediator of immune tolerance arose from long-term pursuit of the molecular and cellular control of transplantation tolerance, versus rejection, in vivo.
As principal investigator, I funded my group through major grant awards, including from the MRC, BHF, NKRF, JDRF, NIHR-i4i, ROTRF, and both local and national Trusts. As my research progressed, key close collaborations developed with Stanford (Randall Morris), Johns Hopkin's (Mike Kastan), Harvard, and Yale. Currently, I hold a Senior Research Associate post in the John van Geest Centre for Brain Repair, University of Cambridge.
As a member of the University's Clinical School, I take a keen interest in students and serve on Faculty and Degree Committees while also promoting new opportunities including the new cross-Schools NanoMed Initiative. My experience includes commercial development of my academic discoveries recognized by the British Technology Group, and more recently, the UK Technology Strategy Board. I own two patents that are shared with Yale, and together with Tarek Fahmy (Yale), have co-founded the spin-out company LIFNanoRx Ltd.
LIF-nanotherapy to promote self-tolerance and myelin repair in multiple sclerosis
Nanotechnology is now recognized as a key platform for health. This GMSI project exploits nanotechnology previously developed by the applicant Su Metcalfe (Cambridge) in collaboration with Tarek Fahmy (Yale) to harness the power of leukaemia inhibitory factor (LIF), a potent stem cell cytokine able to (i) oppose inflammatory immunity, and (ii) promote myelin repair – both highly relevant to the treatment of multiple sclerosis (MS).
A LIF-nano device specifically targeted to immune cells, or neural precursor cells, will be evaluated in a series of preclinical studies where the safety in man is already confirmed for the nano-formulation platform. The LIF-nano formulation permits targeted and sustained delivery of LIF at physiological doses, avoiding LIF's degradation by serum proteases and rapid urinary elimination, and also avoiding off-target effects – LIF having pleiotrophic activity. An entirely novel aspect of the project is the use of LIF-nanotherapy to test potential synergy with lymphodepleting therapy.
We will use the Biozzi ABH mouse model of experimental autoimmune encephalomyelitis (EAE), which provides a reproducible, relapsing–remitting form of EAE that becomes secondary progressive with disease duration, as occurs in clinical MS. Milestone 1 tests the hypothesis that LIF-nano per se may enhance protective auto-immune self-tolerance in EAE. Milestone 2 will identify any synergistic benefit gained by treating with LIF-nano during homeostatic lymphoid recovery following lympho-depletion. Milestone 3 compares efficacy of delivery using the intra-nasal versus intravenous routes.
Co-applicants bring expertise in (i) development of nano-engineered devices for clinical use (Tarek Fahmy, Yale); (ii) use of EAE models in preclinical development of therapy for MS (David Baker, Queen Mary University of London); (iii) models of myelin repair (Anna Williams, Edinburgh); and (iv) advice towards future clinical trials in MS (Gavin Giovannoni, Queen Mary University of London).
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