In a world where vasodilators rule the landscape of treatments for pulmonary arterial hypertension (PAH), scientific research groups and pharmaceutical companies around the world are working to develop targeted therapeutics that focus on specific cellular pathways that are associated with dysfunction in PAH patients. Within the realm of targeted therapeutics, certain therapies are in basic research and others are at moderate-to-advanced stages of clinical trials.
Dr. Bhuvaneshwar Vaidya and Dr. Vivek Gupta at the School of Pharmacy in Keck Graduate Institute acknowledge that targeted therapies are becoming more prevalent in PAH research, largely due to the potential for side effects when patients use current medications. “To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment,” they wrote in a review entitled “Novel Therapeutic Approaches for Pulmonary Arterial Hypertension: Unique Molecular Targets to Site-Specific Drug Delivery,” which was published in Journal of Controlled Release.
Much of the new research in targeted therapeutics for PAH begins with a study to determine if particular proteins are involved in PAH onset or progression by identifying an upregulation in the protein. At Chonbuk National University and Mount Sinai Medical Center, a team of researchers led by Dr. Priya Murugesan and Dr. Dongmei Wu were interested in the kinin B1 receptor. “Kinins are proinflammatory peptides that exert a variety of biological actions via stimulation of two pharmacologically distinct receptor subtypes, B1 and B2,” wrote the team in their article, “Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling,” which was published in Hypertension.
The team had a small-molecule inhibitor, BI113823, that specifically bound to the kinin B1 subtype. Previous work identified that the molecule had anti-inflammatory effects in cardiovascular-derived cells, and they were interested if it could work in the setting of PAH. They induced PAH in rats via monocrotaline injection and treated the rats orally with BI113823 twice a day. Treatment reduced inflammation and signs of PAH onset in the rats that would have normally occurred with an increase in kinin B1 receptors.
Alternatively, researchers may notice a change in a particular protein in the context of PAH disease onset or progression. When proteins are suppressed but the genes associated with them are otherwise intact without mutations, regulators of protein synthesis may be at play. These regulators are known as microRNAs, which are molecules that bind to the mRNA molecules that encode proteins ready to be synthesized. Sometimes microRNAs suppress proteins necessary for proper function, while other times they suppress proteins that are detrimental to function.
In the case of the latter, a group of researchers from Institut Universitaire de Cardiologie et de Pneumologie de Québec led by Dr. Jolyane Meloche and Dr. Sébastien Bonnet noticed an increase in bromodomain-containing protein 4 (BRD4) in the context of PAH pathogenesis. BRD4 was causing an increase in proliferation of cells in the pulmonary arteries, causing a narrowing of the vessels and increase in pulmonary artery pressure. The increase in BRD4 was linked to a decrease in microRNA-204. The team was able to inhibit BRD4 by using a small-molecule inhibitor called JQ1 that was specific to BRD4 or by using siRNA that could mimic the function of microRNA-204 and suppress BRD4 synthesis. In their recently published work, “Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension,” researchers were able to reverse disease progression in rats induced with PAH with these two strategies.
Along with these targeted therapeutic strategies that are still in basic research, experimental PAH therapy bardoxolone methyl is in a Phase 2 clinical trial for PAH. Reata Pharmaceuticals began enrollment last year for the Phase 2 study for the targeted therapeutic bardoxolone methyl that was recently granted orphan drug designation for PAH. There are a few potential ways in which bardoxolone methyl addresses pathological states in PAH. Concerning an increased state of inflammation in PAH, bardoxolone methyl is targeted toward an inflammatory pathway in PAH involving the proteins Nrf2 and NF-κB. It inhibits pro-inflammatory molecules and promotes anti-inflammatory molecules. Regarding oxidative damage in cells, bardoxolone methyl inhibits signaling pathways that lead to reactive oxygen species production, thereby acting as an antioxidant. Additionally, in terms of inefficient energy metabolism in cells, bardoxolone methyl addresses mitochondrial dysfunction by promoting the efficient use of fatty acid and glucose molecules in cells to create ATP. These three mechanisms, as well as potential other signaling events mediated by bardoxolone methyl, may work synergistically as a therapy for patients with PAH.
Drs. Vaidya and Gupta identified another new aspect of targeted therapeutics for PAH that literally “targets” drugs to the site of intended action. This type of drug targeting is based on interactions between molecules linked to drug carriers and molecules present particularly in the area of cell dysfunction in PAH. Similar to how magnets are drawn to each other, the targeted therapeutic is drawn to cells in the area with a need for treatment.
“[Inability] to deliver anti-PAH drugs to the disease site (i.e., distal pulmonary arterioles) has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy,” wrote Drs. Vaidya and Gupta. “Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs.” Accordingly, molecules such as JQ1, BI113823, and bardoxolone methyl could be linked to these carriers to ensure they reach inflamed pulmonary arterioles in patients with PAH. Targeting of this nature is the most specific type of targeted drug delivery and is considered “active targeted delivery.”
There is a much work to be done before scientists identify which specific molecules will serve as ideal targets, but active targeted delivery of PAH-modifying agents is a viable form of therapy in the future. There is a need to continue to research pathways involved with PAH onset and progression in order to cover the span of patients with various dysfunctional cell pathways that lead to PAH.
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