Rendering of molecules

RASP Inhibition

Aldeyra was founded in 2004 to exploit RASP (reactive aldehyde species) as a novel anti-inflammatory target. Aldeyra is the leader in the development of novel RASP inhibitors for the treatment of immune-mediated diseases, such as ocular inflammation and autoimmune diseases.

What are RASP?

Reactive aldehyde species (RASP) are reactive molecules that covalently bind to cellular biomolecules, disrupting their function and activating pro-inflammatory mediators. RASP are formed by a variety of processes, including lipid peroxidation, alcohol oxidation, polyamine and glucose metabolism. 

QUICK FACT

RASP Related Disease

Genetic mutations in the RASP-metabolizing enzymes, which are Aldehyde dehydrogenase enzymes, cause disease.

The Mechanism of RASP

  • RASP effect inflammation signaling via covalent binding to proteins, including receptors and enzymes.
  • RASP-protein adducts directly influence the function of proteins, leading to activation of intracellular inflammatory factors, including NF-kB, an important mediator in the inflammatory response. 
  • In addition, RASP-protein adducts bind to Scavenger Receptor A, which also initiates pro-inflammatory signaling and leads to the formation of antibodies against the adducted protein, at least in part explaining the presence of host-directed antibodies in autoimmune diseases such as rheumatoid arthritis

RASP and Immune-Mediated Disease

Levels of RASP are generally observed to be elevated in ocular and systemic inflammatory disease, and thus represent therapeutic targets for immune-modulation.

Because of the inherent toxicity of RASP, most, if not all, living organisms contain enzymes that convert RASP into non-toxic molecules. Under normal and healthy conditions physiological RASP are metabolized by enzymes preventing reactions with other molecules or proteins. 

Aside from the stimulation of inflammation, there is no generally accepted biological role of high levels of RASP. Some physiologic molecules have RASP forms, including retinaldehyde (a form of Vitamin A) and pyridoxal and pyridoxal phosphate (forms of Vitamin B6), but the activity of physiological RASP is highly restricted by chaperone and other proteins that prevent reaction with other molecules, including our RASP inhibitors. Thus, pharmacotherapeutic RASP inhibition is expected not to adversely affect normal physiologic processes.

Our most advanced RASP inhibitor, reproxalap, which has been administered to hundreds of patients across numerous completed clinical trials, has been observed to be generally well-tolerated and has not resulted in any serious adverse events to date.

Reproxalap – Our Novel RASP Inhibitor Platform

Reproxalap, our lead clinical candidate,  is a novel small molecule RASP inhibitor that covalently binds free aldehydes and diminishes excessive RASP levels. The broad activity and unique mechanism of action (MOA) of reproxalap offers therapeutic promise in wide array of distinct conditions, including immune-mediated diseases and SLS.

Reproxalap’s MOA has been validated with the demonstration of clinical relevant activity in multiple mechanistically distinct late-phase clinical indications.

In in vitro and animal studies, reproxalap does not appear to affect most cellular components, including most receptors, enzymes, ion channels, or other proteins. Reproxalap has been shown to outcompete cellular constituents to covalently bind and trap RASP. Reproxalap-RASP adducts to be rapidly degraded in cellular environments, after which neither reproxalap nor RASP are detectable. 

Outside of biological systems, reproxalap-RASP adducts have shown to be non-reactive and stable, suggesting that reproxalap-RASP binding may be effectively irreversible. By forming covalent drug-RASP adducts that are then degraded, reproxalap and other RASP inhibitors have the potential to substantially lower RASP levels.