Human Pathophysiology and Biotherapeutics

Complex glycans -- located at the surfaces of cells, deposited in the extracellular matrix, and attached to soluble signaling molecules -- play a crucial role in the phenotypic expression of cellular genotypes. We are investigating the indispensable role of these molecules in human physiology as well as in disease processes. Complex glycans act on a multicellular level, at the interface between cells, tissues, and organs, to coordinate biological processes. From a biological perspective, complex glycans represent a promising, but to date largely untapped, source for the development of novel therapeutics. Our lab has been exploring various biotherapeutic applications.

Close observation of the interactions between glycans and the proteins they bind reveals connections between structure and activity. Their interactions are structurally selective and impinge on diverse disease processes. Glycome-level phenomena are crucial players in disease onset and it;s progression in practically all organ systems. Glycan-based strategies for drug development fall into two main categories: restorative therapies and interventions. Restorative therapies seek to replace biomolecules that the body fails to synthesize adequately. Drugs that can intervene in glycan-dependent disease processes represent a novel niche for drug discovery research, where the manipulation of molecular interactions holds the promise of improving patient outcomes.

Cardiovascular Targets: Thrombosis formation is a chief health concern worldwide as it leads to significant patient morbidity and mortality. The creation of efficient and specific inhibitors of blood coagulation remains critical to the appropriate clinical management of thromboses. Heparin, a highly sulfated polysaccharide isolated from mast cells, has been the preferred anticoagulant and antithrombotic agent for more than seven decades. The rational design of low molecular weight heparins (LMWH) with improved in vivo activity is at the forefront of our R & D program.

Pulmonary System: Although heparin and LMWHs have been widely used in treatment as anticoagulants, their broader use has so far been limited by a lack of non-invasive delivery methods for this class of molecules. Our laboratory has demonstrated an efficient, rapid, and reproducible delivery system for heparin through the lungs that is not constrained to particles of a certain geometric or aerodynamic diameter.

Oncology: Cell surface and ECM glycans regulate nearly all aspects of cancer biology -- including tumorigenesis, tumor progression, and metastasis. A particular tumor-derived glycan can be pro-tumorigenic or anti-tumorigenic, largely depending on fine glycan structure. Recent evidence has highlighted the fact that, as part of the transformation process, cancer cells alter their cell-surface glycome profile. This change includes the differential expression of particular proteoglycan-core sequences, and the alteration of GAG fine structure of consitutent proteoglycan chains. Communicative cross-talk in the tumor microenvironment, which is central to oncogenic activity, is largely regulated, and thus could potentially be manipulated, via glycan biomolecules.
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Neurobiology: Oligosaccharide chains of a nervous system origin influence a wide array of biological processes. Through these same processes, glycans play an essential role in neural development. Perhaps the most provocative evidence for the key role of complex polysaccharides in neural development are recent findings demonstrating that these sugars are critical in cytokinesis and morphogenesis during the early embryonic stages of the nematode, Caenorhabditis elegans. Futhermore, glycans have also been implicated as a major deterrent to the regeneration of axons following traumatic injury to the brain and spinal cord. Such injuries typically result in paralysis and the chances for recovery for spinal cord injury patients are infinitesimally small. Our group is exploring various glycan-based strategies geared towards alleviating these conditions.

Biotherapeutics: Glycan-based strategies for drug development fall into two main categories: restorative therapies and interventions. Restorative therapies seek to replace biomolecules that the body fails to synthesize adequately. Drugs that can intervene in glycan-dependent disease processes represent a novel niche for drug discovery research, where the manipulation of molecular interactions holds the promise of improving patient outcomes.