Mike Gait's Lab

(L to R) Kurt Hoogewijs, Andrey Arzumanov, MJG, Liz O’Donovan, Frank Abendroth

Final Powerpoint presentation to LMB Dec 12 2017

Up to 2017 when the group closed, we studied the chemical synthesis and use of cell penetrating peptides (CPPs) as conjugates of modified oligonucleotides, notably peptide nucleic acids (PNA) and phosphorodiamidate morpholino oligonucleotides (PMO), to target pre-mRNA inside cell nuclei as steric blocking agents towards development of therapeutics for treatment of neuromuscular and other genetic diseases.

The group worked closely with Professor Matthew Wood and colleagues at the University of Oxford in the design of novel CPPs and the testing of their PMO conjugates in cells and animals. Applications include:

  1. High level exon skipping of the dystrophin gene and dystrophin restoration in an mdx mouse model of Duchenne Muscular Dystrophy,
  2. Exon inclusion of the SMN2 gene in muscle and brain in mouse models of Spinal muscular atrophy.
  3. Targeting of the expanded repeat sequences in mouse models of myotonic dystrophy.

Initially we developed as series of CPPs called Pip that showed high-level cell delivery and in vivo activity of their conjugated PMOs. Further CPP development has produced several novel peptide series (called D-PEP) that have formed the basis for the start of a new MRC-Oxford University spin-off company for the development of P-PMO conjugates towards clinical trials in neuromuscular diseases. This work is continuing in the Wood laboratory in Oxford.

In the final years of the group we also developed peptide conjugates of PNA for delivery into mitochondria as an antigenomic strategy for treating mitochondrial diseases, devised a novel parallel synthesis method called SELPEPCON for conjugate synthesis and screening, as well as new fluorescent labelling chemistry.