Empreinte thérapeutique pour optimiser les traitements personnalisés en neurodégénérescence

 

Yasser Iturria Medina

Université McGill

 

Domaine : neurosciences, santé mentale et toxicomanies

Programme Chercheurs-boursiers - Junior 1

Concours 2019-2020

Neurodegenerative diseases like Alzheimer's and Parkinson's are extremely complex, presenting concurrent abnormalities in multiple biological factors, including misfolded proteins accumulation (amyloid, tau, alpha-synuclein), vascularization, inflammation and/or cerebral atrophy. Numerous treatment trials targeting only one of these components have failed to achieve significant clinical benefits. Given the multifactorial nature of these neurodegenerative diseases and the marked interpersonal variability, combinations of treatments targeting multiple components might be required to succeed. In keeping with the principles of Personalized Medicine, such multi-target combinations may require tailoring to individual therapeutic needs as opposed to treating all patients with the same approach. In neurodegeneration, unfortunately, we currently do not have clinical tests to tailor personalized interventions across several biological factors.

Prompted by the imperative for individualized treatment of neurodegeneration, we have developed a personalized Therapeutic Intervention Fingerprint (pTIF) approach. The pTIF can integrate a large amount of data (e.g. multi-modal brain imaging, cognitive evaluations) into a simplified individual patient profile of the quantitative biological factor modifications needed to control disease evolution. Our preliminary results in Alzheimer's disease (331 patients) supports that pTIF vastly outperforms cognitive/clinical evaluations when predicting individual gene expression profiles, providing biological validity to the model. Indeed, pTIF-based subgroups of patients present distinctively altered molecular pathways, supporting the identification of dissimilar pathological subtypes and therefore therapeutic needs.

Our project focus on validating extensively the clinical applicability of the pTIF framework in four heterogeneous clinical populations (including both Alzheimer's and Parkinson's disease patients, subjected to different therapeutic treatments). A successful validation across the four heterogeneous populations would represent a turning-point toward biomarker-driven therapeutic interventions and have important implications for selective enrollment in clinical trials. Importantly, we will share the pTIF framework via popular open-access and web-based code hosting repositories, further accelerating international clinical use and the creation-evaluation cycle of effective therapeutic agents for neurodegeneration.