Circadian Neuroendocrine Resetting Therapy (CNRT)
Circadian Neuroendcrine Resetting Therapy (CNRT) represents a treatment modality for improving chronic systemic biological disorders or altering biological states in vertebrate species. This therapeutic approach involves the study and identification of integrated circadian neural activities within specific sites of the central nervous system that are temporally orchestrated in function to regulate physiological activities such as immunity, growth, reproduction, behavior, cardiovascular and renal physiology, and metabolism. This circadian neuroendocrine “blueprint” for modulation of complex physiological activities in multicellular organisms is the quintessential regulator of organismal level biology, integrating and synchronizing the complex biochemical processes of the tissues of the body internally and synchronizing the organism with its cyclic external environment to maximize the probability for health and survival. It should not be difficult to appreciate that environmental or genetic perturbations to these circadian neuroendocrine regulatory systems may have major adverse consequences for the biological integrity and health of the organism. It further follows that “resetting” these aberrant circadian neurophysiological regulatory systems back towards their “normal” temporal organization may lead to improvement of the biological disorders presented by such initial circadian disruption. These circadian neurophysiological interactions are exceedingly complex, yet through the study of comparative physiology, it is possible to unveil key neural systems that have evolved and persisted over long expanses of evolutionary time for the regulation of specific biological functions.
Scientists from Albert H. Meier’s laboratory at Louisiana State University beginning in the early 1960’s were the very first to identify paramount roles for temporal interactions of specific circadian neuroendocrine systems in the regulation of any and multiple different organismal level physiological activities. Advances of such work led to the discoveries of multiple circadian networks that are integrated in specific ways to regulate major aspects of physiology such as cardiometabolic health, development, immunity, reproduction, and behavior. This fundamental information is required in order to “reset” or “fix” aberrations in the circadian neuroendocrine system back towards normal to treat disease, i.e., one needs to know what “normal” circadian neuroendocrine activity maintaining health of the physiology at hand looks like in order to simulate it to improve pathology generated by its disruption. CNRT identifies aberrations in circadian neuroendocrine circuits that potentiate pathologies and uses methods of “resetting” these aberrations back towards a normal circadian organization to treat disease. One such example of a drug development plan that was founded upon this CNRT is the development of morning administration of Cycloset, a quick-release formulation of bromocriptine, a dopamine D2 receptor agonist for the treatment of type 2 diabetes. In brief, it was found that among animals in the wild that undergo seasonal variations in insulin sensitivity, seasonal insulin resistance was characterized by a reduction in the circadian peak of dopamine input to the biological clock, the suprachiasmatic nuclei, that in turn induced neural outputs from these clock neurons to potentiate insulin resistance. Increasing dopaminergic input to the system at this time of day restored insulin sensitivity. The development, formulation and administration of Cycloset was based upon on research of circadian neuroendocrine systems regulating peripheral fuel metabolism. Cycloset improves glycemic control in type 2 diabetes subjects. Such resetting approaches with other methodologies applied to other circadian neural networks can have positive influences on immunological, reproductive, and behavioral disorders as well.
Photodynamic Therapy for the Treatment of Cancer
Photodynamic therapy (PDT) of cancer involves the systemic administration of a tumor-localizing agent that is only toxic when irradiated by light of the appropriate wavelength (photosensitizer). Because tumor destruction requires the geometric presence of the photosensitizer and light, each of which are non-toxic, it is possible to elicit tumor site-specific killing without damage to surrounding tissues. Although the theoretical basis and therapeutic benefit implications of this treatment modality are extremely attractive, in practice, PDT to date has not translated into a board-based successful treatment of neoplastic disease. We have substantially improved the efficacy of PDT by synthesizing new agents that uniquely meet multiple criteria for an effective PDT photosensitizer for the treatment of cancer including:
1. Direct tumor cell killing versus vascular damage
2. High uptake into tumor tissue
3. High discrimination ratio of retention between tumor and normal tissue
4. High efficiency of light absorption in the therapeutic window
5. No photosensitization of skin
6. Low systemic toxicity
7. High Therapeutic Index
8. Strong post-PDT immunization against tumor
Preclinical testing with these agents has demonstrated their ability to destroy large tumor masses beyond the range of light penetration and to elicit anti-tumor immunity. We are pursuing the further development of our lead candidates for clinical testing.