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Gene & Protein in Disease Genetics of arteriovenous malformations

mediators involved in AVM formation at the genetic level the signaling and gene expression abnormalities brought
are effective. on by endothelium Alk1 suppression . Sirolimus uses the
[98]
Bevacizumab is a humanized monoclonal antibody PI3K-Akt-mTOR cascade to inhibit the overactivation of
shown in numerous clinical studies as an anti-angiogenic mTOR in patients with HHT. Sirolimus and nintedanib
therapy for HHT patients due to its ability to bind and (tyrosine kinase inhibitor) function synergistically to
neutralize human VEGF (Figure 3) [89-91] . VEGF has normalize the Smad1/5/8, mTOR, and VEGFR2 pathways
been shown to be implicated in the formation of bAVM and effectively reverse AVM formation in the retina of
[99]
as discussed previously [54,92] . Robert et al. reported that Bmp9-immunodeficient mice .
bevacizumab has been enrolled in an ongoing phase Zhu et al. showed that thalidomide and lenalidomide
III randomized clinical trial involving HHT patients (safer derivative with similar efficacy) treatment in
(NCT03227263) . Zhu et al. also showed that adeno- Alk1-deficient mice not only reduced inflammation and
[41]
associated virus-mediated expression of soluble FMS- hemorrhage in established bAVM but also inhibited
related tyrosine kinase 1 (sFLT-1) can reduce bAVM the development of bAVM via the upregulation of
severity by inhibiting VEGF-dependent downstream the platelet-derived growth factor B (PDGFB) and
signals . platelet-derived growth factor receptor-β (PDGFR-β)
[93]
Using angiopoietin-2 (ANGPT2) monoclonal signaling pathway [102] . Although the role of PDGFB/
antibodies, Crist et al. proved successful alleviation and PDGFRβ signaling in human bAVM pathogenesis is
prevention of AVM formation in Smad4-deficient mice mainly unknown, expression of PDGFRβ was reduced
through inhibition of downstream ANGPT2, which is in bAVM [103] . Somatic activating mutations in the KRAS
an antagonistic ligand of TEK (receptor tyrosine kinase) gene cause excessive activation of the MAPK-ERK
[94]
in the angiopoietin-TEK signaling pathway . Ola et al. pathway in endothelial cells, occasionally leading to
also showed that the inhibition of the PI3K via PI3-kinase sporadic AVM [67,68] . Inhibiting the MAPK-ERK cascade
inhibitors in the PI3K-AKT signaling pathway reverses with MAP-ERK kinase inhibitors may be a promising
established AVM in Alk1-deficient mice models . approach to treating non-hereditary bAVM because
[95]
higher levels of ERK expression were seen in cells with
Disruption of signaling pathways of genes, such as the mutant KRAS protein. Al-Samkari et al. reported on
SMAD4, ALK1, and ENG, as a result of loss-of-function phase II trials (NCT04258046 and NCT05125471) in the
mutations, is causes of HHT [54,96,97] . Tacrolimus and United States and EudraCT 2019‐003573‐26 in Europe
sirolimus, two immunosuppressive medications, have that evaluate the use of trametinib (MEK inhibitor) in
been discovered to activate pathways downregulated in AVM [100] . Nicholson et al. also reported a case study in
forming AVM, suggesting possible therapies for HHT [98,99] . which a patient with CM-AVM was successfully treated
Tacrolimus is a potent stimulator of Smad1/5/8 signaling with trametinib [101] .
in cell and Alk1-deficient mice. Tacrolimus treatment also
alleviated HHT vascular disease in mice and addressed Despite advancements in pharmaceutical therapies
that inhibit AVM formation and progression, open
microsurgical AVM excision is still the most efficient
treatment for bAVM. Pharmacologic therapies are
being developed as adjuncts to surgical resection or
to minimize AVM size and symptoms in individuals
with high-grade AVM and elevated surgical risks. In
the future, customized genomic medicine may be used
as a therapeutic strategy when we have a better grasp
of the genetic abnormalities and signaling pathways
connected to the development of bAVM. Thus, locating
active gene mutations and using inhibitors to target their
signaling pathways are fundamental to personalized AVM
treatment.

8. Options for testing SNPs
Figure 3. VEGF as a therapeutic target. The VEGF receptor, which Genetic testing plays a key role in diagnosing and
is intimately involved in endothelial proliferation, is a key target for
emerging interventions. managing AVM, particularly in patients with HHT, a
Abbreviation: VEGF: Vascular endothelial growth factor. genetic disorder that predisposes individuals to AVMs [104] .

Volume 2 Issue 2 (2023) 10 https://doi.org/10.36922/gpd.0312