Descrizione del progetto
Terapia genica per le malattie polmonari
La carenza di proteina B del surfattante (SP-B) è una rara malattia genetica che provoca grave sofferenza respiratoria nei neonati e può portare a insufficienza respiratoria fino al decesso. Gli approcci di terapia genica adottati finora per sostituire il gene mutato hanno incontrato difficoltà tecniche. Il progetto BREATHE, finanziato dall’UE, intende migliorare gli approcci di terapia genica per la carenza di SP-B attraverso un metodo di consegna dell’mRNA modificato che elimina il rischio di integrazione genomica associato ai vettori basati sul DNA. I ricercatori convalideranno il loro approccio in modelli murini della malattiae applicheranno lo stesso metodo per la terapia della fibrosi cistica, un’altra malattia genetica associata alla produzione di muco denso e appiccicoso nei polmoni, infiammazioni e infezioni ricorrenti.
Obiettivo
Surfactant Protein B (SP-B) deficiency and Cystic Fibrosis (CF) are severe, fatal inherited diseases affecting the lungs of ten thousands of people, for which there is currently no available cure. Although gene therapy is a promising therapeutic approach, various technical problems, including numerous physical and immune-mediated barriers, have prevented successful application to date. My recent studies were the first to demonstrate the life-saving efficacy of repeated pulmonary delivery of chemically modified messenger RNA (mRNA) in a mouse model of congenital SP-B deficiency. By incorporating balanced amounts of modified nucleotides to mimic endogenous transcripts, I developed a safe and therapeutically efficient vehicle for lung transfection that eliminates the risk of genomic integration commonly associated with DNA-based vectors. I also assessed the delivery of mRNA-encoded site-specific nucleases to the lung to facilitate targeted gene correction of the underlying disease-causing mutations. In comprehensive studies, we show that a single application of nucleases encoded by nucleotide-modified RNA (nec-mRNA) can generate in vivo correction of terminally differentiated alveolar type II cells, which more than quadrupled the life span of SP-B deficient mice. Together with my working group, I aim to further develop this technology to enhance the efficiency and safety of nec-mRNA-mediated in vivo lung stem cell targeting, providing an ultimate cure by permanent correction. Specifically, we will test this approach in humanized mouse models of SP-B deficiency and CF. Developing and genetically engineering humanized models in vivo will be a critical step towards the safe translation of mRNA based nuclease technology to the clinic. With my competitive edge in lung-transfection technology and strong data, I feel that my group is uniquely suited to achieve these goals and to make a highly valuable contribution to the development of an efficient treatment.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- engineering and technologynanotechnologynano-materials
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
72074 Tuebingen
Germania