Inhaled DNAI1 mRNA therapy for treatment of primary ciliary dyskinesia

Area of Science:

• Genetics and Molecular Biology
• Respiratory Medicine
• Gene Therapy

Background:

• Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia, leading to debilitating respiratory issues with no current approved therapies.
• Mutations in the DNAI1 gene, crucial for ciliary function, cause up to 10% of PCD cases, resulting in progressive lung damage.
• There is a significant unmet need for treatments that can restore ciliary activity and mucociliary clearance in PCD patients.

Purpose of the Study:

• To investigate the potential of aerosolized mRNA therapy for treating primary ciliary dyskinesia (PCD).
• To assess the efficacy of lipid nanoparticle (LNP)-formulated human DNAI1 mRNA delivery to lung tissues.
• To evaluate the restoration of ciliary function following gene therapy in preclinical models of PCD.

Main Methods:

• Delivery of aerosolized LNP-formulated human DNAI1 mRNA to human bronchial epithelial cell models and nonhuman primate (NHP) lungs.
• Quantification of newly translated human DNAI1 protein levels in NHPs post-aerosolization.
• Assessment of ciliary function rescue in an in vitro cell-based PCD model.

Main Results:

• Successful aerosol delivery of LNP-DNAI1 mRNA to human bronchial epithelial cells and NHP lungs.
• Detectable levels of newly translated human DNAI1 protein were observed in NHPs at relevant doses.
• Restoration of ciliary function was achieved in an in vitro PCD model, demonstrating therapeutic potential.

Conclusions:

• Aerosolized LNP-DNAI1 mRNA delivery is a viable strategy for targeting PCD.
• This approach shows promise for restoring ciliary function and addressing the underlying cause of PCD.
• Further clinical development of inhaled DNAI1 mRNA therapy is warranted for PCD treatment.