Heritable pulmonary arterial hypertension (
HPAH) is a serious lung
vascular disease caused by heterozygous mutations in the
bone morphogenetic protein (BMP) pathway genes, BMPR2 and SMAD9. One noncanonical function of BMP signaling regulates biogenesis of a subset of
microRNAs. We have previously shown that this function is abrogated in patients with
HPAH, making it a highly sensitive readout of BMP pathway integrity.
Ataluren (
PTC124) is an
investigational drug that permits ribosomal readthrough of
premature stop codons, resulting in a full-length
protein. It exhibits oral bioavailability and limited toxicity in human trials. Here, we tested
ataluren in lung- or blood-derived cells from patients with
HPAH with
nonsense mutations in BMPR2 (n = 6) or SMAD9 (n = 1).
Ataluren significantly increased BMP-mediated
microRNA processing in six of the seven cases. Moreover, rescue was achieved even for mutations exhibiting significant nonsense-mediated mRNA decay. Response to
ataluren was dose dependent, and complete correction was achieved at therapeutic doses currently used in clinical trials for
cystic fibrosis.
BMP receptor (BMPR)-II
protein levels were normalized and
ligand-dependent phosphorylation of downstream target Smads was increased. Furthermore, the usually hyperproliferative phenotype of pulmonary artery endothelial and smooth muscle cells was reversed by
ataluren. These results indicate that
ataluren can effectively suppress a high proportion of BMPR2 and SMAD9
nonsense mutations and correct BMP signaling in vitro. Approximately 29% of all
HPAH mutations are nonsense point mutations. In light of this, we propose
ataluren as a potential new personalized
therapy for this significant subgroup of patients with PAH.