title: Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. .
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Drake
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dunmore
authors.forename: Lauren N
authors.initials: LN
authors.lastname: McNelly
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018389:Codon, Nonsense; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000494:pharmacology*; D065627:Familial Primary Pulmonary Hypertension; D005786:Gene Expression Regulation / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051904:Smad8 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D015507:Drugs, Investigational; D035683:MicroRNAs; D010069:Oxadiazoles; C107514:SMAD9 protein, human; D051904:Smad8 Protein; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C515878:ataluren