Moving lentiviral-based gene therapy into a first-in-man CF trial.

Griesenbach U, Alton EW, Beekman JM, Boyd AC, Chan M, Davies JC, Davies LA, Davidson HE, Dekkers JF, Gea-Sorli S, Gill DR, Hasegawa M, Higgins T, Hyndman L, McLachlan G, Inoue M, Hyde SC, Moran C, Meng C, Paul-Smith MC, Pringle IA, Pytel KM, Rodriguez-Martinez A, Stevenson BJ, Tsugumine S

Pediatric Pulmonology, Volume 50, Issue S41, Abstract 243

The North American Cystic Fibrosis Conference, Phoenix, 2015

The UK CF Gene Therapy Consortium has developed a pipeline of vectors to deliver CFTR into the airway epithelium.

The first of these (plasmid/liposome complexes) recently completed a Phase IIb trial. Anticipating that increased efficiency of gene transfer will be required, we have developed an F/HN-pseudotyped lentivirus which is ~2  logs more efficient in lung gene transfer than non-viral vectors, a single administration lasts for the lifetime of a mouse, and can be repeatedly administered.

This vector is targeted for a first-in-man study in 2016, and in preparation for this we have assessed:-

  1. selection of the most efficient promoter/enhancer for lung gene transfer.
  2. assessment of toxicity  “benchmarked” against the leading non-viral formulation including mapping of integration sites.
  3. determination of transduction efficiency which will be used to inform dose-ranging in the trial and characterisation of  the cell types transduced by the vector.
  4. understanding the impact of pre-existing and acquired anti-viral immunity on transduction efficiency and toxicity.
  5. confirmation of CFTR expression and function in relevant models.
  6. comparison of vector stability in a jet and single-pass mesh nebuliser.

Data will be presented for each of these components, which we believe support progression into human studies. Trial design as well as a regulatory-compliant toxicology study will also be discussed.