Peptide conjugated oligonucleotides for splice switching therapy of Spinal Muscular Atrophy

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, arising from loss-of-function of the SMN1 gene. Mutations in SMN1 result in motor neuron degeneration, accompanied by peripheral manifestations including skeletal muscle atrophy. SMA is rare with an incidence of ~1:10,000 live births; however 1 in every 35 unaffected individuals is likely to be a carrier for the disease. Most affected SMA infants typically have a severe form of the disease with a mean life expectancy of ~2 years in age. However children with less severe disease can survive beyond 2 years but with poor quality of life. SMA severity relates directly to the level of functional SMN protein that a patient produces. A closely related gene to SMN1 is SMN2, although this gene typically only produces ~10% of fully functional SMN protein. However some SMA patients have additional copies of the SMN2 gene, and hence can produce more functional SMN protein. This mitigates disease severity and such patients typically have a milder disease course. Most SMN2 gene product is not functional because the gene generates two distinct mRNAs via alternative splicing i.e. most of the mRNA lacks exon 7 and generates only partially functional protein. A HIGHLY NOVEL TREATMENT has been developed which acts on SMN2 mRNA to influence inclusion of exon 7 to generate functional SMN protein. This treatment utilizes splice switching oligonucleotides (SSOs), which are chemically modified DNA fragments that bind specifically to the SMN2 mRNA. SSO therapy has shown great potential in recent years for the disorder Duchenne muscular dystrophy (DMD) where they are now in advanced clinical trials. An SSO therapy has potential for even greater impact in SMA because it has potential to treat nearly 100% of affected SMA patients.The major challenge to successful development of an SSO therapy for SMA is delivery of the SSO drug to critically affected tissues including motor neurons and skeletal muscle. Delivery to the spinal cord typically requires invasive methods, while targeting important peripheral tissues, such as skeletal muscle, is inefficient and often requires high SSO concentrations. The current state-of-the-art, led by Isis Pharmaceuticals, involves a clinical trial in which SSO is administered invasively to SMA patients via injection into the fluid surrounding the spinal cord and which therefore does not treat peripheral tissues.Our aim is to develop an advanced SSO that can be administered non-invasively through a simple intravenous injection to treat peripheral tissues and also penetrates sufficiently well into the brain and spinal cord to treat the neurological component of the disease. We have developed advanced SSOs to which are coupled short protein fragments (peptides) to facilitate improved SSO delivery to peripheral tissues and provide penetration into the brain and spinal cord. A key initial step is to select the optimal peptide. Building on our existing peptide platform, we will also study a number of additional peptides with high brain delivery potential. Once a candidate peptide and SSO has been selected we will conduct extensive studies into the tissue distribution and tissue concentration of the SSO drug and also into the optimal dosing requirements. This information will allow us to design a multi-dose, long-term SSO therapy regimen to systemically treat all tissues associated with SMA, and we will evaluate this rigorously in an animal model of SMA. Our previous success with treating DMD and experience with peptide chemistry in relation to SSO drugs makes us uniquely well-placed for success in this project. Success will be followed by steps towards clinical development of the lead SSO drug.