Spinal Muscular Atrophy..PMO's Best in Class of AO's...
Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.
CSR, Isis recently released functional Motor Score data on a small group of cohorts [1-9mg/kg] suffering from Spinal Muscular Atrophy. These scores demonstrated a small improvement in function after one dose. Caution, no placebo cohort so the results are hard to evaluate. There have been several test drugs that have demonstrated promise for SMA in early trials but all have failed to show benefit when an actually scientific study with negative controls have been followed. Isis seems to be stuck at low doses due to related toxicity. Their compound was injected intrathecally so it is an interesting pathology to administer AO's for exon-skipping. Regarding preclinical studies of 2'MOE's Vs. PMO's it looks like the PMO's produced more SMA-1 protein. Intrathecal injection of the PMO for use in the CNS sounds very intriguing because the one negative pharmaceutical property of this anionic AO [PMO] is it's rapid renal clearance. The patent landscape...I haven't looked at it.