How agile is medicine today in responding to rare or new diseases? We all know that the red tape surrounding clinical trials and the approval of new drugs today is significant; but, of course, it is only proper that the strictest standards are in place to ensure public safety.
The unprecedented development and approval of COVID-19 vaccines demonstrate that medicine can be very agile—and effective—when the hour demands it. However, the COVID-19 pandemic crippled the world and the world was crying out for an immediate medical solution; when it comes to rare diseases, advocates are few and far between, and the fear of unexpected side effects sometimes trumps therapeutic innovation.
Read more about PAH epidemiology
Pulmonary arterial hypertension (PAH) is a rare disorder in which extensive vascular remodeling and pulmonary artery vasoconstriction occur, often leading to right-sided heart failure and death. Current therapies target improvements in functional capacity and pulmonary hemodynamics. They target 1 of 3 pathways:
- The cyclic adenosine monophosphate (cAMP) pathway
- The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway
- The endothelin-1 (ET-1) pathway
New experimental therapies for PAH promise to target specific molecular pathways that are associated with the pathophysiology of the disease. Ronald Zolty, MD, PhD, a researcher from the University of Nebraska Medical Center in Omaha, recently published a detailed review in the Journal of Experimental Pharmacology of novel experimental therapies currently under investigation for PAH. We will look at some of these therapies here in this article.
A Landscape of New Pathways
One focus within the development of novel PAH therapies is the various inflammatory pathways in PAH. Studies show PAH is associated with various autoimmune diseases and immunosuppression improves clinical outcomes in patients with PAH and certain systemic autoimmune diseases. Now, new therapies attempt to disrupt inflammation by directly targeting proinflammatory cytokines, such as Interleukin-6, Interleukin-1, and tumor necrosis factor-α.
Therapeutic agents are also being developed to target the platelet-derived growth factor (PDGF) and tyrosine kinase (TK) pathways. PDGF has been implicated in stimulating the proliferation of fibroblasts and pulmonary artery smooth muscle cells (PASMCs), while TK is likewise associated with the pathophysiology of PAH. Currently, the most important drug that targets this pathway is imatinib, originally a chemotherapy drug used to treat chronic myeloid leukemia. Studies have shown that imatinib significantly improves right ventricular function, although concerns about serious adverse effects remain.
Another target of new therapies is the RhoA/Rho-kinase inhibitors signaling pathway. Rho-kinase belongs to a family of enzymes involved in regulating various cellular responses, including smooth muscle tone. Rho-Rho kinase activation can ultimately result in vasoconstriction, and studies have shown that inhibiting RhoA/Rho-kinase signaling can cause significant vasodilation in hypoxia-induced mice. Fasudil, a drug currently being developed to inhibit RhoA/Rho-kinase signaling, has demonstrated the ability to reverse pulmonary vascular remodeling.
Another pathway that is the target of current research is the bone morphogenetic protein receptor-2 (BMPR2) signaling pathway. Studies have found that BMPR2 plays a protective, antiinflammatory role in promoting the survival of pulmonary arterial endothelial cells (PAECs) and inhibiting the proliferation of PASMCs. BMPR2 dysfunction can cause pulmonary vascular remodeling, though its exact mechanisms are unknown. One of the drugs targeting this pathway is tacrolimus, a potent BMPR2 activator that reverses pulmonary vascular remodeling and endothelial dysfunction in PAH patient cells.
In recent years, growing research has implicated mitochondrial dysfunction in the pathophysiology of PAH. It is thought that mitochondrial dysfunction in PAH increases lactic acid production and uncoupled glycolysis at the expense of glucose oxidation and pyruvate production. This causes metabolic imbalances that are characteristic features of PAH. Many therapies are under development to restore proper mitochondrial function and to reverse damage caused by mitochondrial dysfunction.
Read more about PAH prognosis
Oxidative stress is also implicated in PAH pathophysiology, in that it causes vascular wall thickening and triggers vasoconstriction. In addition, it seems that oxidative stress increases with disease severity, meaning that oxidative stress markers can potentially be used to monitor disease progression. Since oxidative stress is also implicated in a number of other diseases, such as cancer and Alzheimer’s disease, many therapies are concurrently being developed to neutralize the effects of oxidative stress in the body.
As well all know, the remodeling of the extracellular matrix (ECM) is a critical feature of PAH. Collagen and elastin are the main components of the ECM, and they help control cell shape and maintain cell-cell communication. When ECM regulation breaks down, it allows the migration and proliferation of PASMCs, resulting in the pathogenic remodeling of the pulmonary vasculature. Currently, therapies are being developed to block metabolic pathways that lead to ECM dysfunction.
Other Therapeutic Approaches
Current experimental PAH therapies each target a component that makes up the mosaic of PAH pathophysiology, but emerging therapies can go a step further by eliminating the root biological problem altogether. Gene mutation or abnormal gene expression are among the causes of PAH; gene therapy would utilize the delivery of therapeutic nucleic acids into the cells of a patient, with potentially massive therapeutic implications. Epigenetics, an emerging field of biology, can also help shed some light on what triggers PAH and how the disease can be avoided.
Although we know a lot more about PAH than we did a decade ago, substantial gaps in our understanding of the disease remain. The way forward? “To improve comprehension of the PAH pathobiology and to discover new molecules capable of disrupting the disease and its development,” Dr. Zolty concluded.
Zolty R. Novel experimental therapies for treatment of pulmonary arterial hypertension. J Exp Pharmacol. Published online August 17, 2021. doi:10.2147/JEP.S236743
Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006;99(7):675-91. doi:10.1161/01.RES.0000243584.45145.3f