Therapeutic applications of synthetic oligonucleotide analogues & their peptide conjugates
Our work focuses on the chemical synthesis and use of cell penetrating peptides 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.
In conjunction with Professor Matthew Wood and colleagues at the University of Oxford, we designed a new class of cell-penetrating peptides, called Pip, that have shown outstanding cell and in vivo delivery of conjugated PMO. 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 a mouse model of Spinal muscular atrophy. 3) targeting of the expanded repeat sequences in mouse models of myotonic dystrophy. We have continued to develop such cell-penetrating peptides further towards obtaining clinical candidates. The new D-PEP peptides form the basis of founding of a new MRC-University of Oxford spin-off company to take P-PMO to clinical trials.
- L. O’Donovan, I. Okamoto, A. A. Arzumanov. D.L. Williams. P. Deuss and M.J. Gait (2014)
Parallel synthesis of cell-penetrating peptide conjugates of PMO towards exon skipping enhancement in Duchenne muscular dystrophy.
Nucleic Acids Therapeutics 25: 1-10.
- K. Hoogewijs, A.M. James R.A.J. Smith, M.J. Gait, M.P. Murphy and R. Lightowlers (2016)
Assessing the delivery of mitochondria-targeted molecules using Click chemistry.
ChemBioChem. 17: 1312-1316.
- F. Shabanpoor, S. M. Hammond, F. Abendroth, G. Hazell, M.J.A. Wood and M.J. Gait (2017)
Identification of a peptide for systemic brain delivery of a morpholino oligonucleotide in mouse models of spinal muscular atrophy.
Nucleic Acids Therapeutics 27: 130-143.
- Andrey Arzoumanov
- Frank Abendroth
- Richard Raz