In utero gene editing for monogenic lung disease

Area of Science:

• Pulmonary Medicine
• Gene Therapy
• Developmental Biology

Background:

• Monogenic lung diseases stem from surfactant gene mutations, leading to severe respiratory failure or chronic lung disease with limited treatments.
• Current therapeutic options for these inherited lung disorders are scarce, particularly for conditions presenting at birth.

Purpose of the Study:

• To evaluate the efficacy of in utero gene editing for treating monogenic lung diseases.
• To assess the potential of CRISPR-Cas9 delivery via intra-amniotic injection during fetal development.

Main Methods:

• Developed a CRISPR fluorescent reporter system for precise gene editing in fetal lungs.
• Administered CRISPR-Cas9 gene editing reagents into the amniotic fluid of pregnant mice during fetal development.
• Utilized a mouse model with a mutation in the SFTPC gene (SFTPC^I73T) to test therapeutic intervention.

Main Results:

• In utero gene editing predominantly targeted pulmonary epithelial cells, including alveolar type 1, alveolar type 2, and airway secretory cells, with high and persistent editing.
• CRISPR-Cas9-mediated inactivation of the mutant SFTPC^I73T gene in utero improved lung morphology in treated fetuses and postnatal mice.
• The in utero gene editing strategy significantly increased survival rates in mice with the lethal interstitial lung disease model.

Conclusions:

• In utero gene editing is a viable strategy for precise and targeted gene correction in fetal lungs.
• This approach offers a potential therapeutic solution for monogenic lung diseases that are lethal at birth.
• The study provides proof-of-concept for prenatal gene therapy as a treatment for severe inherited respiratory conditions.