Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh)
Apstrakt
Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs alpha). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G alpha s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their ...significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning.
Ključne reči:
drug repurposing / ectopic ossification / Hedgehog pathway inhibitors / mesenchymal progenitor cells / Progressive Osseous HeteroplasiaIzvor:
GENETIKA-BELGRADE, 2019, 51, 1, 347-355Izdavač:
- Društvo genetičara Srbije, Beograd
DOI: 10.2298/GENSR1901347G
ISSN: 0534-0012
WoS: 000467414400029
Scopus: 2-s2.0-85066009658
Institucija/grupa
Tehnološko-metalurški fakultetTY - JOUR AU - Gvozdenović-Jeremić, Jelena AU - Mojović, Ljiljana PY - 2019 UR - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/4255 AB - Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs alpha). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G alpha s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning. PB - Društvo genetičara Srbije, Beograd T2 - GENETIKA-BELGRADE T1 - Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh) EP - 355 IS - 1 SP - 347 VL - 51 DO - 10.2298/GENSR1901347G ER -
@article{ author = "Gvozdenović-Jeremić, Jelena and Mojović, Ljiljana", year = "2019", abstract = "Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs alpha). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G alpha s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning.", publisher = "Društvo genetičara Srbije, Beograd", journal = "GENETIKA-BELGRADE", title = "Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh)", pages = "355-347", number = "1", volume = "51", doi = "10.2298/GENSR1901347G" }
Gvozdenović-Jeremić, J.,& Mojović, L.. (2019). Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh). in GENETIKA-BELGRADE Društvo genetičara Srbije, Beograd., 51(1), 347-355. https://doi.org/10.2298/GENSR1901347G
Gvozdenović-Jeremić J, Mojović L. Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh). in GENETIKA-BELGRADE. 2019;51(1):347-355. doi:10.2298/GENSR1901347G .
Gvozdenović-Jeremić, Jelena, Mojović, Ljiljana, "Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (poh)" in GENETIKA-BELGRADE, 51, no. 1 (2019):347-355, https://doi.org/10.2298/GENSR1901347G . .