Splicing mutations in the human growth hormone (hGH) gene (GH-1) that cause skipping of exon 3 result in a form of GH deficiency termed Isolated Growth Hormone Deficiency type II (IGHD II). The GH-1 gene contains 5 exons; constitutive splicing produces the wild type 22kDa hormone while skipping of exon 3 results in transcripts encoding a 17.5 kDa isoform that acts as a dominant negative to block secretion of the wild type hormone. Common characteristics of IGHD II include short stature due to impaired bone elongation growth and, in severe cases, anterior pituitary hypoplasia. Typically, IGHD II is treated by subcutaneous delivery of hGH which can rescue stature but, unfortunately, does not inhibit pituitary hypoplasia. Direct destruction of transcripts encoding the dominant negative 17.5 kDa isoform should both rescue stature and prevent hypoplasia. Here, we have used delivery of short hairpin RNAs (shRNAs) to rescue a murine model of IGHD II by specifically targeting transcripts encoding the 17.5 kDa isoform using RNA interference. To our knowledge, this is the first example where an shRNA has been expressed to specifically degrade an incorrectly spliced transcript and rescue a dominant negative disease phenotype in vivo.