Spinal muscular atrophy (SMA), is a severe childhood disease most commonly caused by the homozygous loss of the survival motor neuron 1 (SMN1) gene that encodes an essential protein, SMN. A homologous gene, SMN2 provides insufficient levels of SMN and is unable to compensate for the loss of SMN1. A single nucleotide change in SMN2 exon 7 creates a splice silencer, leading to the predominant production of truncated transcripts missing exon 7 that encode a non-functional SMN protein. Pre-mRNA splicing of SMN2 exon 7 is modulated by RNA-binding proteins SAM68 and hnRNP-A1 that promote exon 7 exclusion from the mature SMN2 transcript. Targeted knockdown of SAM68 and/or hnRNP-A1 has potential to increase the amount of functional SMN produced by the sub-optimal SMN2 gene. Antisense oligonucleotides designed to knockdown SAM68 and hnRNP-A1 were delivered individually and in combination with Anti ISS-N1, an antisense compound targeting SMN2 directly, into SMA patient fibroblasts. Gene transcript and functional protein analysis showed SAM68 and hnRNP-A1 knockdown subsequently increased functional SMN production in an additive manner when combined with Anti ISS-N1. There is thus potential for antisense therapeutics targeting SAM68 and/or hnRNP-A1 to be used to augment the action of Anti ISS-N1 as a combinatorial treatment for SMA.