Our Science

We are seeking to unlock the full therapeutic potential of the nitric oxide-cGMP pathway to design differentiated next-generation sGC stimulators for serious and orphan diseases.

Nitric Oxide Signaling

The Central Biological Role of Nitric Oxide Signaling

Nitric oxide is a short-lived signaling molecule that is produced locally under exquisite physiological control throughout the body. Nitric oxide signaling plays a central role in real-time regulation of diverse biological systems. Its discovery was recognized as the basis for the 1998 Nobel Prize in Physiology or Medicine.

Nitric oxide signaling is mediated through its receptor, soluble guanylate cyclase (sGC), an intracellular protein in tissues throughout the body, including in the vasculature, kidney, brain, lung, heart, liver, adipose and skeletal muscle. As locally produced nitric oxide diffuses into adjacent target cells, it binds to sGC. sGC then catalyzes the conversion of guanosine – 5’ – triphosphate (GTP), a source of energy for protein synthesis, to cyclic guanosine monophosphate (cGMP), increasing production of this secondary signaling molecule.

Growing Understanding of Nitric Oxide-cGMP Pathway’s Role in Health and Disease

Our understanding of the role the nitric oxide-cGMP pathway plays in health and disease continues to grow, informed in large part by seminal discoveries pioneered by the founding Cyclerion team. While initial breakthroughs revealed a critical role for this pathway in regulating smooth muscle and vascular function, emerging insights suggest this pathway is responsible for regulating other diverse and critical biological functions as well, including inflammatory and fibrotic processes, metabolism and neuronal function.

The specificity of nitric oxide-sGC-cGMP signaling in health (i.e., not all of the pathways are activated in all tissues at all times) is accomplished by both local production of nitric oxide and control of the expression and activity of pathway components in distinct cell types.

Deficient Nitric Oxide Signaling is Broadly Linked to Disease

A wide range of cardiovascular, metabolic, inflammatory, fibrotic and neurological diseases are associated with deficient nitric oxide signaling. When the bioavailability of endogenous nitric oxide is reduced in disease states, normal physiological function is disrupted and signaling pathways are imbalanced, leading to vasoconstriction, inflammation and fibrosis.

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We believe that the growing understanding of the nitric oxide-cGMP signaling pathway’s role in diverse aspects of health and disease creates the potential for a new generation of important therapeutics for serious and orphan diseases that we believe remains largely untapped.

Our Approach

Preferentially Increasing Nitric Oxide Signaling in Disease-Relevant Tissues

We are capitalizing on the breadth of this pathway’s potential by designing small molecule sGC stimulators that, by their unique properties, preferentially increase nitric oxide signaling in disease-relevant tissues. sGC stimulators act synergistically with nitric oxide on sGC to boost production of cGMP. Our sGC stimulators are highly differentiated from each other, as well as from other sGC modulators and molecules that target this pathway via other mechanisms.

Restoring the Nitric Oxide-cGMP Pathway Holds Potential to Treat Many Diseases

We believe our approach to restoring the nitric oxide-cGMP pathway represents a potential therapeutic target for powerful pharmacological intervention in many serious and orphan diseases characterized by deficient nitric oxide signaling.

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Applications Beyond Deficient Nitric Oxide Signaling

In addition, the potential utility of sGC stimulation is not restricted to diseases associated with a loss of nitric oxide signaling. Preclinical studies suggest that enhanced nitric oxide pathway signaling may provide therapeutic benefit in diseases associated with inflammation, fibrosis or metabolic dysregulation, regardless of whether there is a direct role for the nitric oxide pathway dysfunction in the pathogenesis of the disease.

Robust Pipeline of Five sGC Stimulator Programs

We are advancing a pipeline of five differentiated sGC stimulator programs whose properties are tailored for distinct serious and orphan diseases with significant unmet clinical need. Areas of initial focus include sickle cell disease (SCD), cardiometabolic diseases, neurodegenerative diseases, liver diseases and pulmonary diseases.

Explore our pipeline programs

Clinically Validated Mechanism to Harness the Nitric Oxide-cGMP Pathway

Of the clinically validated means to modulate nitric oxide-cGMP pathway signaling (nitric oxide-generating compounds, PDE5 inhibitors, and sGC stimulators), we believe sGC stimulation represents the optimal mechanism to realize the full therapeutic potential of this pathway.

Direct nitric oxide-generating compounds, such as nitroglycerin and nitrates, have several limitations including tolerance (reduction in effect over time), which has not been observed with sGC stimulators. PDE5 inhibitors rely on significant signaling (flux) through the pathway to have effects, which limits the tissues in which they can have a pharmacological effect.

sGC stimulators are agonists of sGC that work synergistically with nitric oxide to amplify signaling through the pathway, providing opportunity to expand the pharmacology to any tissue in which nitric oxide signaling is occurring. We are investigating sGC stimulators to better understand and unlock their therapeutic potential across a myriad of serious and orphan diseases.

References

The Central Biological Role of Nitric Oxide Signaling

Growing Understanding of Nitric Oxide-cGMP Pathway’s Role in Health and Disease

Deficient Nitric Oxide Signaling is Broadly Linked to Disease

Restoring the Nitric Oxide-cGMP Pathway Holds Potential to Treat Many Diseases

Clinically Validated Mechanism to Harness the Nitric Oxide-cGMP Pathway

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