Peptide conjugated oligonucleotides for a phase I/IIa clinical trial in Spinal Muscular Atrophy

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 autosomal recessive disease with an incidence of ~1:10,000 live births. Most affected SMA infants typically have a severe form of the disease with a mean life expectancy of ~2 years in age (SMA Type I). However children with less severe disease (SMA Type II and III) can survive beyond 2 years but with severe mobility problems and comorbidities (respiratory insufficiency; scoliosis; failure to thrive) that limit normal functioning and survival. 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 as the copy number of this latter gene is polymorphic in the general population, 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. The most effective therapy currently for SMA is splice modification of the SMN2 pre-mRNA through use of SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) to increase levels of SMN protein. SSOs are single-stranded, DNA-like molecules that can bind to and alter the processing of SMN2 pre-mRNA to generate functional copy of the gene. A SSO (Nusinersen) which modifies SMN2 splicing to generate functional SMN protein has recently been approved for clinical use by the FDA and EMA. While this represents a major development for SMA, this first generation SSO does not penetrate the blood brain barrier (BBB) and is therefore administered through repeated invasive intrathecal injections into the fluid around the spinal cord. This is necessary for adequate spinal cord drug delivery but is not practical as a long-term therapy and moreover it also fails to treat systemic features of the disease, especially important in severe cases. The major challenge to successful development of an SSO therapy for SMA is systemic delivery of the SSO drug to all affected tissues involved in disease pathogenesis in addition to motor neurons, including peripheral tissues such as skeletal muscle and neuromuscular junctions, liver and autonomic nerves. We have developed a novel platform technology based on short cell penetrating peptides, which when attached to SSOs via direct chemical attachment provide highly effective penetration into cells and into tissues such as the brain and spinal cord and muscles which are exceptionally difficult to reach for large SSO drugs. The major OBJECTIVE of the current project is therefore to identify, develop and test an advanced NEXT GENERATION peptide-SSO for SMA. To achieve this we will: - Select the most suitable peptide based on further study of ~5 peptide-SSO candidates to determine their activity and safety properties in mice - Take this lead peptide-SSO and carry out a full safety assessment of the drug in two species (rats and non-human primates) as required by the Medicines and Healthcare Regulatory Agency, in order to obtain approval to undertake a clinical trial in SMA patients - Carry out a first-in-man phase I/IIa clinical trial in 12 less severely affected Type II and III SMA patients, who represent the most prevalent SMA patients, many of whom are not eligible candidates for intrathecal administration of drugs due to spinal abnormalities. This clinical trial will determine safety and inital effectiveness of the drug and will be a prelude to more detailed studies in larger numbers of patients