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Gene therapy for rare surfactant protein deficiencies

D R Gill(1) K Miah(1) A R Ruffle(1) M A Viegas(1) E Castells(1) H Dolatshad(1) S G Sumner-Jones(1) R Dean(1) E Thornton(2) C McDougall(2) C McLaughlin(2) Y Du(1) A McStea(1) R J Munday(1) A M Munis(1) G McLachlan(2) S C Hyde(1)

1:University of Oxford; 2:The Roslin Institute, University of Edinburgh

We have developed a lentiviral platform for gene delivery to the lung, based on recombinant Simian Immunodeficiency Virus (rSIV) pseudotyped with Sendai virus F and HN glycoproteins (rSIV.F/HN). The receptor for F/HN is present on many lung cell types and lentiviral integration is particularly beneficial for the multiple stem/progenitor cell niches in the lung, to ensure that vector expression is not lost during cell division. These features make rSIV.F/HN a promising platform for treatment of rare lung diseases.

Surfactant Protein Deficiency in term babies is ultra-rare. Pathogenic mutations in genes encoding Surfactant Protein B (SP-B), or lipid transporter ABCA3, result in severe respiratory distress and lung collapse in newborns. Mechanical ventilation is required at birth for survival and no treatment options are available to prolong life for these babies.

We are investigating the rSIV.F/HN platform to deliver SP-B and ABCA3 to progenitor alveolar type II (ATII) cells that produce lung surfactant. The target ATII cells can be transduced in surfactant cell culture models grown at the Air-Liquid Interface and ex vivo in human precision-cut lung slices. For in vivo correction, we delivered rSIV.F/HN expressing human SP-B to a conditional mouse disease model and showed extended (>11 months) survival compared with a median of 5 days in untreated control animals. We have also used ventilated neonatal piglets to model vector delivery to babies via the endo-tracheal tube. Together these data support the development of rSIV.F/HN for treatment of surfactant protein deficiency in neonates.

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