Background

Target

Background

In stroke, activation of TLR-4 produces a cascade of events which ends with the release of inflammatory cytokines such as IL-1, IL-8, TNF-alpha and IL-12 resulting in inflammation and cellular damage. The Neurovascular Research Unit laboratory led by Dr. Ignacio Lizasoain (Universidad Complutense de Madrid) was the first to describe the role of TLR-4 in stroke (Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke, Caso et al, Circulation 2007).

The aim is to develop drug candidates working as antagonist of TLR-4 ligands, blocking receptor activation and therefore the inflammatory response. The resulting drugs may be used at Emergency Units within 48 hours after an episode of stroke and a dose will be administered to the patient in order to prevent inflammation at the adjacent areas to the ischemic core, preventing the death of neurons and reducing brain damage. The drug may be co-administered with other drugs with complementary mechanism of action such as thrombolytics.

AptaTargets licensed-in a group of aptamers as TLR-4 antagonists based on the outstanding advantages of these type of molecules. Within the therapeutic field, aptamers have arisen as a clear alternative to antibodies. Due to their particular chemical and biological properties, aptamers possess a series of advantageous features over antibodies, including: high reproducibility, stability at room temperature, lower costs related to manufacturing and quality control (extremely relevant for the manufacturing of cGMP batches, with an important reduction of production costs allowing higher profitability); minimal immunogenicity (aptamers do not trigger immune reactions, which is a key factor facilitating authorizations from drug agencies) and easy customization and smaller size (which allows for an improved blood-brain barrier penetrability, tissue distribution and target binding).

Circulation

Clinical Perspective

" The innate immune system is able to recognize many pathogens, even without prior exposure, that trigger specific immune responses such as, among others, the synthesis of inflammatory cytokines and the production of reactive species that induce oxidative stress. In this context, toll-like receptors (TLRs) are key components of the innate immune system, and function as receptors that recognize ligands from microbial products, but also from damaged cells and tissues, and thus act as an endogenous danger signal. Innate immune response is largely mediated by leukocytes, such as neutrophils, macrophages, and dendritics cells. Interestingly, some evidence indicates that innate immunity and subsequent inflammatory mechanisms participate in several facets of brain injury. Taking into account that stroke is the one of the leading causes of death, and the main cause of severe long-term disability in adults, and that treatment is often limited to fibrinolysis, a therapy useful to a very low percentage of patients, immunomodulation strategies arise as a possible powerful approach for stroke treatment. Among TLRs, TLR4 is the most frequently observed and best-characterized receptor. Our data show that TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult. The present results also demonstrate that TLR4 signaling is involved in ischemic brain damage through the expression of the inflammatory mediators inducible nitric oxide synthase, cyclooxygenase-2, interferon-regulatory factor 1, and matrix metalloproteinase-9. Considering that the immune response takes place early after the injury, the development of therapies capable of TLR4 signal inhibition could provide a potent neuroprotective effect for acute stroke treatment. "