Science & Technology

RASP: A Novel Therapeutic Target

In response to stimuli such as infection, injury, chemicals, and heat. Reactive Aldehyde Species (RASP) are generated through different metabolic processes that include alcohol oxidation, lipid oxidation (enzymatic and non-enzymatic), and certain metabolic pathways involving polyamines and sphingosine. RASP molecules play a crucial role in inflammation signaling by binding covalently to sulfur- and nitrogen-containing residues on proteins, including receptors and enzymes. RASP binding affects the function of proteins, triggering the activation of inflammatory factors within cells, including NF-κB and inflammasomes, which are vital in the inflammatory response.

Moreover, RASP-protein adducts also bind to Scavenger Receptor A, initiating pro-inflammatory signaling and contributing to the formation of antibodies against the modified proteins, a mechanism that partly explains the presence of host-directed antibodies seen in autoimmune conditions such as rheumatoid arthritis. Elevated levels of RASP are typically observed in ocular and systemic inflammatory diseases, which are the focus of our RASP modulator pipeline. Additionally, RASP are linked to metabolic and neurodegenerative disorders and, besides promoting inflammation, can lead to DNA damage, metabolic aggregate accumulation, and other pathological consequences.

Due to the inherent toxicity of RASP, most living organisms possess enzymes such as aldehyde reductases and aldehyde dehydrogenases that convert RASP into harmless compounds. Genetic mutations affecting these RASP-metabolizing enzymes can result in diseases such as Sjögren-Larsson Syndrome, where mutations in fatty aldehyde dehydrogenase lead to skin, neurological, and retinal issues.

Aside from increasing inflammation, high levels of RASP do not have a widely accepted biological function. Although some physiological molecules have RASP forms (e.g., retinaldehyde, pyridoxal, and pyridoxal phosphate), the activity of such molecules is tightly regulated by chaperone proteins, preventing reaction with other molecules, including our drug candidates. Clinical trials with our RASP modulators, such as reproxalap (administered as an ophthalmic solution) and ADX-629 (administered orally), have demonstrated an acceptable tolerability profile without serious adverse events. The Clinical results support the potential safety and efficacy of pharmacotherapeutic RASP modulation without adversely affecting normal physiological functions.