Abstract
Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in SOX18. Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.
Highlights
Human mutations in the SOX18 gene give rise to Hypotrichosis-Lymphedema-Telangiectasia and Renal syndrome (HLTRS) (Irrthum et al, 2003; Moalem et al, 2015)
Based on the observation that a previous case of HLTRS may have benefited from a long-term exposure to propranolol (Wunnemann et al, 2016), we considered propranolol therapy for another HLTRS patient (Bastaki et al, 2016) in an attempt to mitigate the severity of his symptoms
The patient was diagnosed with HLTRS at 11 months of age, after presenting with alopecia, edema and telangiectasia (Bastaki et al, 2016)
Summary
Human mutations in the SOX18 gene give rise to Hypotrichosis-Lymphedema-Telangiectasia and Renal syndrome (HLTRS) (Irrthum et al, 2003; Moalem et al, 2015). Most disease-causing SOX18 mutations lead to a premature truncation at the C-terminus due to an early stop codon, producing defective protein products that act in a dominant negative fashion. The mutated SOX18 protein can still bind to chromatin but fails to recruit its protein partner(s) to transactivate target genes, and thereby disrupts the endogenous function of SOX18. The dominant-negative mutant prevents other SOX transcription factors to act redundantly and rescue the molecular pathway (Hosking et al, 2009).
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