Descrizione del progetto
Progettazione in silico e valutazione sperimentale di terapie a base di RNA per le pneumopatie
Le terapie a base di RNA comprendono una nuova classe di farmaci che utilizza molecole di RNA per trattare o prevenire le malattie. Le terapie che si basano sull’interferenza dell’RNA operano mediante un meccanismo naturale di silenziamento di geni specifici. Nonostante il potenziale della terapia a base di RNA per il trattamento di bersagli farmacoresistenti nel polmone, le formulazioni di RNA esistenti sono instabili per la somministrazione per via inalatoria. Finanziato dal Consiglio europeo della ricerca, il progetto RatInhalRNA intende migliorare la terapia a base di RNA per i disturbi polmonari. I ricercatori utilizzeranno strategie di dinamica molecolare e apprendimento automatico in combinazione con la sintesi dei polimeri e la caratterizzazione fisico-chimica per ottimizzare le nanoparticelle ai fini della somministrazione di terapie a base di RNA ai polmoni.
Obiettivo
The overarching goal of RatInhalRNA is to computationally predict and develop efficient formulations for pulmonary RNA therapy. New RNA formulations are imperative for clinical RNA delivery beyond the liver. The lung offers undruggable targets which could be treated with RNA therapeutics. However, approved siRNA formulations are not suited for pulmonary delivery due to instability in lung surfactant and during nebulization. Hence, it is my aim to rationally design inhalable and biocompatible polymer-based siRNA formulations for efficient siRNA delivery to the lung.
While biomaterials are commonly optimized empirically via one-variable-at-a-time experimentation, I am the first to combine Design-of-Experiments (DoE) with Molecular Dynamics (MD) Simulations and Machine Learning (ML) to accelerate the discovery and optimization process of siRNA nanocarriers towards the metrics of gene silencing efficacy and biocompatibility at reduced wet-lab resources.
In RatInhalRNA, I will synthesize amphiphilic polyspermines and will prepare siRNA-loaded nanoparticles by microfluidic assembly for experimental assessment of physico-chemical parameters as well as in vitro and in vivo gene silencing efficacy in coronavirus infection models. I will assess siRNA binding of the polyspermines via MD simulations and will analyze the contribution of the nanoparticle design factors on experimental and computational readout responses of the DoE. I will train a support vector machine for supervised ML and will generate models to identify areas of interest. Based on the predictions, I will test additional formulations to obtain a validation dataset for the assessment the ability of the ML algorithm to identify design properties of efficient siRNA nanoparticles for pulmonary delivery.
RatInhalRNA will enable me to predict favorable siRNA nanoparticle characteristics in the future prior to polymer synthesis thereby reducing experimental work and improving sustainability and animal welfare.
Campo scientifico
- medical and health scienceshealth sciencesinfectious diseasesRNA virusescoronaviruses
- natural sciencesbiological sciencesgeneticsRNA
- engineering and technologynanotechnologynano-materials
- engineering and technologyindustrial biotechnologybiomaterials
- natural sciencescomputer and information sciencesartificial intelligencemachine learning
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
80539 MUNCHEN
Germania