Rescue of lethal SP-B deficiency in a murine model using lentiviral vector-mediated gene therapy

Objectives

We assessed our SIV lentiviral vector pseudotyped with Sendai Virus F and HN glycoproteins (rSIV.F/HN) for treatment of ultra-rare Surfactant Protein-B (SP-B) deficiency. Surfactant, comprising lipids and proteins, including SP-B, promotes efficient gas exchange and prevents alveolar collapse. The lack of functional SP-B at birth leads to lethal respiratory distress in full-term infants, requiring long-term ventilation. Without lung transplantation these babies succumb to disease within the first year of life. 

Results

A widely used, conditional, mouse model of SP-B deficiency was utilised. Following removal of protective Doxycycline from the diet, the disease state is induced and mice survive for a median of only 5 days (mice are humanely culled at 15% weight loss). We administered rSIV.F/HN expressing human SP-B via intranasal inhalation to the lungs of these mice and showed that the treatment prolonged survival for >11 months (compared with untreated control animals; P=0.0001). Our longest surviving treated animals remain alive >340 days post-disease induction. The risk of severe respiratory distress in treated animals was reduced (Hazard Ratio 9.3; 95% CI 2.9-30.2) with survival (60.6%) indistinguishable from non-disease induced littermates (74.2%) (P=0.5144).

Conclusions

These data demonstrate enduring survival in this mouse disease model after treatment with rSIV.F/HN expressing human SP-B to restore surfactant homeostasis in the lung. These data also support the development of this lentiviral platform as a potentially curative gene therapy for babies born with surfactant protein deficiencies. We are currently planning toxicology studies to support a clinical trial.