Isolated growth hormone deficiency type II (
IGHD II) is a rare genetic splicing disorder characterized by reduced
growth hormone (GH) secretion and short stature. It is mainly caused by autosomal dominant-negative mutations within the
growth hormone gene (GH-1) which results in missplicing at the
mRNA level and the subsequent loss of exon 3, producing the 17.5-kDa GH
isoform: a mutant and inactive GH
protein that reduces the stability and the secretion of the 22-kDa GH
isoform, the main biologically active GH form. At present, patients suffering from
IGHD II are treated with daily
injections of recombinant human GH (rhGH) in order to reach normal height. However, this type of replacement
therapy, although effective in terms of growth, does not prevent the toxic effects of the 17.5-kDa mutant on the pituitary gland, which may eventually lead to other hormonal deficiencies. As the severity of the disease inversely correlates with the 17.5-kDa/22-kDa ratio, increasing the inclusion of exon 3 is expected to ameliorate disease symptoms. This review focuses on the recent advances in experimental and therapeutic strategies applicable to treat
IGHD II in clinical and preclinical contexts. Several avenues for alternative
IGHD II therapy will be discussed including the use of
small interfering RNA (
siRNA) and
short hairpin RNA (
shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of
histone deacetylase inhibitors (HDACi) and
antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway.