Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions
Abstract
:1. Introduction
2. BMP9/10 Signalling
3. Aetiology of HHT Disease
4. Overlap** Endothelial Cell Abnormalities in HHT and Spontaneous BAVMs
5. Treatment Options for HHT
5.1. Increasing Expression of ENG or ACVRL1 Genes
5.2. Increasing BMP9/10 Ligand Availability
5.3. Targeting Proangiogenic Growth Factor Signalling
5.4. β-Blockers
5.5. Enhancing Pericyte–Endothelial Cell Interactions
6. Summary and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug | Target | Number of HHT Patients | Outcomes | Reference |
---|---|---|---|---|
Bevacizumab (Avastin) | Anti-VEGFA antibody | 24 | Reduced epistaxis and improved cardiac function in liver VM patients with HOHF | [49] |
Bevacizumab (Avastin) | Anti-VEGFA antibody | 238 | Reduced epistaxis | [50] |
Tacrolimus (FK506) | Increased activation ACVRL1 | 24 (+24 placebo) | Reduced epistaxis | [51] |
Pazopanib | TKI | 7 | Some improvement in Hb and epistaxis | [52] |
Timolol | β-adrenergic blocking agent | 28 (+28 placebo) | No change in epistaxis | [53] |
Thalidomide | Increased PDGFB expression | 7 | Reduced epistaxis | [38] |
Drug | Target | Mouse Model | Outcomes | Reference |
Wortmannin, Pictilisib | PI3K inhibitor | Acvrl1-iKOe and Eng-iKOe neonates | Reduced retinal AVMs | [17,37] |
Nintedanib and Sirolimus | TKI and mTOR inhibitor | Neonatal antibody blockade of BMP9/10 | Combination therapy reduced and reversed retinal AVMs | [54] |
DC101 | Anti-VEGFR2 antibody | Eng-iKOe adult | Prevents AVMs and HOHF | [43] |
G6.31 | Anti-VEGFA antibody | Acvrl1-iKOe adult | Prevention of wound induced dermal AVMs; possible reversal of established wound AVMs | [55] |
Sorafenib and Pazopanib analogue (GW771806) | TKI | Acvrl1-iKOe adult | Each drug alone significantly improved Hb and GI bleeding but did not prevent wound-induced skin AVMs. | [56] |
SU5416 | VEGFR2 inhibitor | Eng-iKOe neonate | Significant reduction in retinal AVM size | [37] |
Thalidomide | Increased PDGFB expression | Eng+/− and Acvrl1-iKO adult | Increased SM coverage of dermal and cerebral vessels, reduced cerebral haemorrhage | [38,57] |
LC10 | ANGPT2 inhibitor | Smad4-iKOe neonate | Prevents retinal AVMs | [58] |
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Snodgrass, R.O.; Chico, T.J.A.; Arthur, H.M. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes 2021, 12, 174. https://doi.org/10.3390/genes12020174
Snodgrass RO, Chico TJA, Arthur HM. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes. 2021; 12(2):174. https://doi.org/10.3390/genes12020174
Chicago/Turabian StyleSnodgrass, Ryan O., Timothy J. A. Chico, and Helen M. Arthur. 2021. "Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions" Genes 12, no. 2: 174. https://doi.org/10.3390/genes12020174