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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. 


 

Other Abstracts by these authors
A phase IIb Double-Blind Placebo-Controlled Trial of Non-Viral Gene Transfer for Cystic Fibrosis.
Pringle IA et al.
The American Society of Gene and Cell Therapy Annual Conference (2014) Clinical Development of an Optimal F/HN Pseudotyped SIV Vector for Cystic Fibrosis Lung Gene Therapy.
Pringle IA et al.
The American Society of Gene and Cell Therapy Annual Conference (2014) Secreted Gaussia Luciferase Is a More Sensitive Reporter Than Firefly Luciferase for Non- Viral Gene Transfer to Airway Epithelium Ex Vivo and In Vivo.
Griesenbach U et al.
The American Society of Gene Therapy Annual Conference (2009) A clinical study to evaluate the safety and efficacy of pGM169/GL67A administered to the nose and lungs of individuals with cystic fibrosis.
Hyde SC et al.
The American Society of Gene and Cell Therapy Annual Conference (2010) Update on the UK CF Gene Therapy Consortium Multidose, Non-viral, Gene Therapy Trial
Alton EW et al.
The North American Cystic Fibrosis Conference (2012) Assessment of F/HN-Pseudotyped Lentivirus in a Clinically Relevant Vector for Lung Gene Therapy
Griesenbach U et al.
The North American Cystic Fibrosis Conference (2012)