Novel Therapeutic Strategies for the Treatment of Respiratory Diseases

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Review
11 October 2022
Gene therapy for cystic fibrosis: Challenges and prospects
Hongshu Sui
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Mingjiu Luo
CFTR mutation types and CREIPSR-based Gene Editing. CRIPSR/Cas editing approaches rely on the generation of double stranded DNA break (DSB) and the following repair via non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ can be used for the allele specific repair of splicing mutation in the intronic sequence, such as the 3272-26A>G (c.3140–26A>G) and 3,849 + 10kbC>T (c.3718–2477C>T) CFTR mutations. Homology-independent targeted insertion (HITI) is an approach based on NHEJ. Theoretically, HITI can universally address all CFTR variants independent of genotypes, the donor DNA can be a splicing acceptor associated CFTR cDNA sequence to be inserted into the intronic sequence of CFTR to reconstitute a mutation free mini gene, or a CFTR expression cassette to be inserted into the safe harbor of the chromosome, such as AAVS1. Homology-directed repair (HDR) requires a template for HR to correct point mutation or small deletion/deletion. Base editing and prime editing do not require the generation of DSB and DNA template for correction. Base editing is only used to correct single base point mutation, and primer editing can be used to correct point mutation as well as short deletion/insertion. Same as HDR, the correction options of base editing and prime editing are mutation dependent.

Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.

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Frontiers in Pharmacology

Research and Innovation Approaches to Personalized Pharmacotherapies for Respiratory Diseases
Edited by Paolo Montuschi, Barbara Ruaro, Andrea Motta
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28 April 2025
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