Colchicine in Familial Mediterranean Fever: mechanism of action, resistance and development of an alternative drug – Colemara

Colchicine is a microtubule (MT)-depolymerizing drug used in autoinflammatory diseases including familial Mediterranean fever (FMF). The anti-inflammatory action of colchicine is still poorly understood with three proposed mechanisms: specific action on i) the pyrin inflammasome ii) neutrophils iii) on hepatocytes with an indirect, hepatokine-mediated, systemic anti-inflammatory effect.
Colchicine has a narrow therapeutic window associated with toxicity and leading to poor observance. In addition, a poorly understood resistance mechanism limits its use in a subset of patients. Despite these drawbacks, colchicine use is expanding. It is thus urgent to better understand its anti-inflammatory mechanisms, and the mechanism of colchicine resistance. Furthermore, colchicine analogues with a decrease toxicity/lack of resistance mechanism hold great promise to favour observance, improve patient treatment and limit socio-economical costs associated with colchicine intolerance and resistance.
In this project we focus on FMF, a well-characterized monogenic autoinflammatory disease associated with an hyperactivated pyrin inflammasome, with the main objectives to:
1-Understand the mechanism of colchicine resistance in patients
2-Understand the role of MT in the pyrin inflammasome and how colchicine acts in FMF
3-Develop a novel MT-depolymerizing agent as a safe and effective alternative to colchicine.
This project is based on cohorts of colchicine-resistant and sensitive patients, on in-vitro and ex-vivo experiments and on a mouse model of FMF.
This project should lead to i) decipher the molecular bases of colchicine resistance with the perspective to diagnose and/or counteract this resistance, ii) understand the role of MT and colchicine in normal and FMF pyrin inflammasome activation, iii) the preclinical validation of a novel MT-destabilizing agent with a better therapeutic index than colchicine and potentially no resistance mechanism.