URGENT – Finding the Right Route to the Lung: Unlocking pRecision Gene EditiNg Therapies for Cystic Fibrosis

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Designação do Projeto | Project Name | URGENT – Finding the Right Route to the Lung: Unlocking pRecision Gene EditiNg Therapies for Cystic Fibrosis

Código do Projeto | Project Code | 2024.13775.PEX

Domínio Científico | Scientific Domain | Bioengineering and Biotechnology

Entidade beneficiária | Beneficiary Entity | iBET – Instituto de Biologia Experimental e Tecnológica

Data de início | Starting Date | 01/01/2026

Data de conclusão | Conclusion Date | 30/06/2027

Custo total elegível | Total Eligible Cost | 59 943,52€

Apoio financeiro público nacional | National Public Financial Support | 59 943,52€

Breve Descrição do Projeto | Brief Project Description |

Cystic Fibrosis (CF) is a life-threatening genetic disorder affecting over 160,000 individuals worldwide and is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The W1282X-CFTR mutation is the second most prevalent nonsense mutation in CF, and people with CF (pwCF) carrying this mutation do not benefit from the currently approved CFTR modulator therapies. Gene editing offers a revolutionary path toward a cure, but traditional CRISPR/Cas9 approaches pose risks of large insertions, deletions, and chromosomal instability due to DNA double-stranded breaks (DSBs). Adenine base editing (ABE) is a safer alternative, enabling precise A-to-G corrections without inducing DSBs.

Multiple studies, including our own, have successfully restored CFTR function in W1282X-mutant cells using ABE. However, the challenge remains: delivering these gene-editing tools safely and efficiently to the lungs.

Engineered virus-like particles (eVLPs) offer a breakthrough solution by packaging ABE as transient ribonucleoprotein (RNP) complexes, eliminating risks associated with viral genome integration. By leveraging envelope glycoprotein pseudotyping, eVLPs can be tailored to target specific lung epithelial cells, addressing a critical gap in CF therapy. The URGENT project pioneers this approach, optimizing eVLP tropism to maximize therapeutic impact. This research advances gene editing strategies toward a safe and effective cure for CF, particularly for patients with nonsense mutations.