The goal of this study is a pre-clinical evaluation of nonsense readthrough as a potential therapy for inherited vascular disorders caused by mutations in the bone morphogenetic protein signaling pathway. We will evaluate two drugs with complementary properties. Ataluren is a FDA-designated orphan drug in phase 3 trials for two genetic disorders. It promotes readthrough of nonsense mutations without affecting the level of mRNA transcript and is most effective against UGA stop codons. Amlexanox is an anti-allergy drug that also promotes nonsense readthrough, but does so by inhibiting nonsense- mediated mRNA decay. Information on its codon specificity is limited, but it may show higher activity than ataluren against UAG codons. We will test the comparative effects of these two compounds on mutations that underlie two distinct but related vascular disorders: hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH). The mutation spectrum in these two disorders in complementary, with UGA codons predominating in PAH, whereas UAG/UAA mutations are more common in HHT. PAH is a life-threatening and incurable disease affecting the lung vasculature that is in desperate need of new therapies to tackle the underlying molecular changes that drive vascular remodeling. HHT affects blood vessels throughout the body and has high morbidity associated with arteriovenous malformations in the lungs and brain. Rarely, HHT patients may also develop PAH. We will utilize a combination of (a) a novel dual-tag in vitro reporter construct that we have developed to measure readthrough efficiency and sequence the resulting protein product, (b) patient-derived endothelial cells with defined genetic mutations to study functional restoration of cell signaling and (c) a novel knock-in mouse model with a nonsense mutation for in vivo testing. In the US alone, correction of nonsense mutations could benefit 6000-12,000 people affected with HHT and up to 1000 with PAH. Successful completion of this study will establish the effectiveness of this approach in vivo and define the sub-groups o patients most likely to respond. In addition, the novel dual-tag reporter that we have developed to measure both the efficiency of readthrough and the nature of the amino acid that is incorporated will be generalizable to many other genetic disorders The results of this study could translate rapidly to interventional human trials and pave the way for personalized approaches to therapy for genetic vascular diseases.
This study will evaluate a new therapeutic approach known as nonsense readthrough, testing two drugs that may be able to correct genetic defects in an important cell signaling pathway. Mutations in this pathway can lead to two serious disorders affecting the blood vessels. Hereditary hemorrhagic telangiectasia (HHT) is an inherited abnormality of the blood vessels that can lead to serious bleeding, including strokes. Pulmonary arterial hypertension (PAH) is an incurable and potentially life-threatening disease affecting the blood vessels in the lungs. If successful, this therapeutic approach might also be applicable to many other genetic diseases. The long term goal of this study is identify new therapies for inherited vascular diseases, leading to future clinical trials and the possibility of personalized therapy based on the type of genetic mutation.