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 have designed and tested a new class of Pip peptides 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. In addition, the group devises peptide synthetic methods also e.g. new methods of parallel synthesis, labelling and attachment of novel functions to enhance activities.
- Betts, C., Saleh, A.F., Arzumanov, A.A., Hammond, S.M., Godfrey, C., Coursindel, T., Gait, M.J., and Wood, M.J.A. (2012)
Pip6-PMO, a new generation of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for Duchenne muscular dystrophy treatment.
Molecular Therapy Nucleic Acids 1: e38.
- Järver, P., O’Donovan, L. and Gait, M.J. (2014)
A chemical view of oligonucleotides for exon skipping and related drug applications.
Nucleic Acids Therapeutics 24: 37-47.
- Shabanpoor, F., McClorey, G., Järver, P., Saleh, A.F., Wood, M.J.A. and Gait, M.J. (2014)
Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy.
Nucleic Acids Research 43: 29-39
- Andrey Arzoumanov
- Frank Abendroth
- John Offer