Lentiviral gene therapy for fatal ABCA3 surfactant protein deficiency

ABCA3 surfactant protein deficiency is a rare recessive disorder causing fatal respiratory distress in full-term babies, or interstitial lung disease in early childhood. Mutations in ABCA3 interrupt lipid packaging into lamellar bodies prior to release of surfactant into the alveoli. Any surfactant produced has an altered composition making it inefficient at reducing lung surface tension. In the UK, palliative care is the only option for infants diagnosed with severe ABCA3 deficiency at birth. Here, recombinant Simian Immunodeficiency Virus (rSIV) pseudotyped with Sendai virus F and HN glycoproteins (rSIV.F/HN) was evaluated for ABCA3 expression and correction of ABCA3 deficiency. rSIV.F/HN directed dose-dependent ABCA3 expression in human H441 lung cells (MOI 1-40) and in murine lungs in vivo (BALB/c; n=5 per dose). Phenotypic correction was evaluated by detoxification of doxorubicin (10mM) in H441 cells engineered to overexpress ABCA3 mutations. Cell viability (MTT assay) was reduced by 5-12% in doxorubicin-treated ABCA3-mutant cells (compared with wild-type) but was restored by treatment with rSIV.F/HN expressing ABCA3. To mitigate potential side effects of off-target ABCA3 expression, new promoters driving alveolar-restricted gene expression were evaluated. In vivo imaging of luciferase expression in murine lungs (BALB/c; n=10 per group) showed expression was significantly more restricted (compared with e.g. the Ef1a-derived hCEF promoter; p<0.0001) with minimal loss in overall lung expression (p>0.05). Vector configuration will be further investigated in ABCA3-knockout murine and cell models. These studies support the potential for a lentiviral vector expressing ABCA3 in alveolar cells as a new treatment modality for ABCA3 surfactant protein deficiency.