Q&A: Asporin linked to ‘more favorable disease profile’ in patients with PAH
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Key takeaways:
- In PAH lung samples, researchers observed elevated asporin levels and found a link between these levels and lower disease severity.
- Novel therapeutic targets in PAH are still needed in today’s world.
Asporin has been discovered as a potential new target that may be used when developing therapeutic interventions for pulmonary arterial hypertension, according to a University of California, Los Angeles (UCLA) press release.
This finding came out of a study published in Circulation that evaluated 96 lung samples from patients with PAH and 52 lung samples from individuals without PAH. In the PAH samples, researchers observed elevated asporin levels and found a link between these levels and lower PAH severity.
Researchers that played an important role in the study included co-first authors, Jason Hong, MD, PhD, assistant clinical professor at David Geffen School of Medicine at UCLA, and Lejla Medzikovic, PhD, postdoctoral researcher at David Geffen School of Medicine at UCLA, as well as senior author, Mansoureh Eghbali, PhD, professor in the department of anesthesiology at UCLA.
Healio spoke with Hong to learn more about asporin, current targets in PAH therapeutic interventions and plans for future research.
Healio: What is asporin? Why are higher levels of asporin favorable?
Hong: Asporin is part of a family of proteins called small leucine-rich proteoglycans (SLRPs), which are known for their role in regulating the extracellular matrix (ECM).
In our research, we discovered that asporin is upregulated in the lungs and blood of patients with PAH and is associated with a more favorable disease profile.
Higher levels of asporin appear to counteract the pathological remodeling of the pulmonary vasculature that characterizes PAH. This protective role suggests that asporin may help limit the progression of the disease by inhibiting detrimental cellular processes such as proliferation in the pulmonary arteries.
Healio: What are the current targets in therapeutic interventions for PAH? What are key drugs that have been developed using these targets?
Hong: Current therapeutic interventions for PAH primarily target three main pathways: the endothelin pathway, the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway and the prostacyclin pathway.
Drugs targeting the endothelin pathway include endothelin receptor antagonists (ERAs) like macitentan (Opsumit, Actelion Pharmaceuticals) and ambrisentan (Letairis, Gilead), which help reduce vasoconstriction. The NO-cGMP pathway is targeted by phosphodiesterase-5 (PDE5) inhibitors such as sildenafil (Revatio, Viatris) and tadalafil (Adcirca, United Therapeutics), which enhance vasodilation. The prostacyclin pathway is targeted by prostacyclin analogs such as epoprostenol and treprostinil, as well as prostacyclin receptor agonists such as selexipag (Uptravi, Johnson & Johnson), which promote vasodilation and inhibit platelet aggregation.
Additionally, sotatercept (Winrevair, Merck), now FDA-approved and in clinical use, targets the transforming growth factor (TGF)-beta pathway, helping to rebalance the dysregulated signaling involved in vascular remodeling. This new therapeutic option offers significant promise for PAH patients.
Despite these advancements, PAH remains a progressive and often fatal disease, underscoring the need for continued research and the development of novel therapeutic targets.
Healio: Why is the discovery of elevated asporin promising in the development of new therapies for patients with PAH?
Hong: The discovery of elevated asporin in PAH patients is promising because it identifies a novel target that may offer a new therapeutic avenue beyond the currently targeted pathways. Our findings suggest that asporin has a protective effect in PAH, potentially by inhibiting key pathological processes such as pulmonary artery smooth muscle cell proliferation. Targeting asporin, or enhancing its activity, could provide a new strategy for slowing or reversing the progression of PAH, addressing an unmet need for more effective treatments.
Healio: You also found that asporin inhibits proliferation and transforming growth factor-beta/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells in PAH lungs. What are the dangers of transforming growth factor-beta/phosphorylated SMAD2/3 signaling in PAH?
Hong: TGF-beta signaling, particularly through the phosphorylated SMAD2/3 pathway, plays a critical role in the pathogenesis of PAH. This signaling pathway drives the excessive proliferation of pulmonary artery smooth muscle cells, leading to the thickening and stiffening of the pulmonary arteries, which contributes to increased pulmonary vascular resistance and right ventricular failure. Unchecked activation of this pathway exacerbates the vascular remodeling that underlies the progression of PAH.
Our study’s finding that asporin inhibits TGF-beta/phosphorylated SMAD2/3 signaling suggests that it may help mitigate these harmful processes, offering a promising therapeutic benefit.
Unlike sotatercept, which targets other ligands in the TGF-beta superfamily, asporin specifically binds to the TGF-beta ligand itself, preventing its activation of the signaling cascade. This distinction highlights how different therapeutic agents can target the same pathway in unique ways, potentially offering complementary strategies for managing PAH.
Healio: How do you plan to build off of what you found in this study in future research?
Hong: Moving forward, we plan to investigate the precise mechanisms by which asporin exerts its protective effects in PAH, particularly its interactions with key signaling pathways such as TGF-beta. We are also interested in exploring the therapeutic potential of asporin in preclinical models, with the ultimate goal of developing asporin-based therapies for PAH. Additionally, we aim to conduct studies in larger patient cohorts to validate asporin as a clinical biomarker, which could guide personalized treatment strategies for PAH patients.
We believe that the discovery of asporin’s role in PAH represents an important step forward in our understanding of the disease’s complex biology. This finding underscores the value of integrative multiomic approaches in uncovering novel therapeutic targets.
We are excited about the potential of asporin to lead to new treatment strategies that could improve outcomes for patients with PAH, a disease that remains challenging to treat with current therapies.
References:
- Hong J, et al. Circulation. 2024;doi:10.1161/CIRCULATIONAHA.124.069864.
- UCLA-led study unveils new insights and potential treatments for pulmonary hypertension. https://www.uclahealth.org/news/release/ucla-led-study-unveils-new-insights-and-potential-treatments-2. Published Aug. 21, 2024. Accessed Aug. 22, 2024.