Systemic delivery of SMA therapy: Partly funded through SMA Europe’s 4th Call for Research Proposals, Dr. Suzan Hammond from the Matthew Wood laboratory in Oxford and her team have published their study on the use of peptides to deliver antisense oligonucleotides effectively to target tissues bodywide.
SMA results from reduced levels of a protein called survival motor neuron (SMN) because of the loss of function of the SMN1 gene which codes for it. However, humans have a back-up gene called SMN2 which produces some SMN protein, albeit not enough to compensate for the SMN1 deficiency. Molecules called splice-switching oligonucleotides (SSOs) have been shown to increase the amount of protein produced by SMN2 by correcting a mechanism called “splicing”. The development of such compounds is now a clinical reality for SMA. However, delivering these oligonucleotides to the central nervous system (CNS) is difficult, so current approaches have been restricted to using invasive intrathecal injections.
In her study, Dr. Hammond shows that an oligonucleotide, coupled with a specific peptide, called Pip6a-morpholino phosphorodiamidate oligomer (PMO), demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice, through systemic administration. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 days to a mean of 456 days, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord and normalisation of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.
S. M. Hammond, G. Hazell, F. Shabanpoor, A. F. Saleh, M. Bowerman, J. N. Sleigh, K. E. Meijboom, H. Zhou, F. Muntoni, K. Talbot, M. J. Gaitb and M. J. A. Wood. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2016 Sep 12. pii: 201605731.