With a focus on coronary microvascular dysfunction/disease (CMD), Lucier Pharmaceuticals is developing novel drugs to address unmet clinical needs of managing microvascular diseases in different organs. Our drug candidate(s) are based on a theoretical breakthrough in the arteriolar function regulation by a research team at Texas A&M University, which resulted in a patent application and newly-identified druggable target(s).
Background: No regulatory–approved effective therapy for treating microvascular dysfunction and/or diseases is currently available. Examples of such conditions are 1) microvascular angina, aka coronary microvascuar dysfunction/disease (CMD); 2) microvascular stroke; 3) side effects from anti-cancer therapies (e.g. radiation, chemotherapy, kinase inhibitors, and antibody drugs) due to damages to normal vascular function. Despite well-established clincial evidence, knowledge on which molecules and/or molecular signaling pathways are involved in the abnormal microvascular constriction, and drug- or treatment-induced microvascular dysfunction is very limited. Experimental study of such conditions at microcirculation level is needed to better understand druggable target(s) before designing an improved treatment solution. However, due to technical challenges in studying microvessels, e.g., visualizing/imaging/isolating, network complexity, and the limited available tissue for molecular characterization, the advance in microvascular research has been either linear or stagnating over the past decade. Consequently, the knowledge on the mechanism of microvascular dysregulation was mainly extrapolated from studies in large conduit vessels or cultured vascular/non-vascular cells.
Technical Note: Microvessels are susceptible to physical manipulations, and great care during isolation preparation is necessary to preserve viability and vasomotor function such as the development of spontaneous basal tone. Most vascular biology research laboratories have commonly used pharmacological vasoconstrictors such as a thromboxane analog (U46619), prostaglandin F2, KCl, and ET-1, to induce an “artificial basal tone” in vessels that fail to develop a spontaneous basal tone. These preconstrictors can lead to inaccurate information on vasoreactivity and responsiveness, and also evoke confounding signaling molecules because of triggering/mingling/superimposing of additional pathways that mask or alter the original vascular behavior and signal transduction. This concern is especially true in the study of large arteries because they do not display a significant level of basal tone or in microvessels that fail to develop basal tone, preconstrictors are inevitably added in order to study the vasodilation mechanisms. Furthermore, super high vasoconstriction agonists such as 10 nM or above ET-1 was used in most of such experiments.
Technoloigical advantage: From Dr. Kuo’s lab (https://medicine.tamu.edu/faculty/kuo.html) at Texas A&M Univeisty, isolated microvessels from rat, pressure-overload mice, healthy and diabetic pig and human tissue samples (with proper consenting) are studied. In our experimental setting, arterioles generally have tonic response without using any vosoconstrictors; then picomolar (pM) ET-1 consistenly caused constriction. The arterioles (< 100 µm in diameter) isolated from the heart, brain, retina, skeletal muscle, or mesentery develop spontaneous basal tone without using any pharmacological constrictors, and these vessels exhibit normal dilation to endothelium-dependent agonists (bradykinin or serotonin) mimicking vasomotor behavior observed in vivo. These criteria are prerequisites for every study we have performed. Based on the technoloigical advantage over many other research labs, we are reasonably confident that our data and proposed mechanism are more closely reflect microvessel functional regulation than well-established arterial constriction based on studies of large artery, during which pre-constriciton and unphysiological concentrations of agnosits were used.
Our approach: Utilizing our strength in the field of microvascular research, Lucier Pharmaceuticals addresses broad unmet clinical needs by focusing on the understanding of microvascular regulation and dysregulation from both functional and molecular perspectives. We are developing novel therapies based on scientific evidence. With our well-established research capability using the pig animal model, resembling the human organ system, Lucier provides pre-clinical services to the pharmaceutical companies to identify potential unwanted side effects to microvessels from their drug candidates.