Eric Shusta

The blood vessel network of the brain is comprised of specialized endothelial cells that separate the bloodstream from the brain interior. These brain endothelial cells are so impermeable that the brain vasculature is oftentimes referred to as the blood-brain barrier (BBB). As a result of its barrier properties, the BBB plays an extremely important role in central nervous system (CNS) homeostasis by protecting neurons from fluctuations in blood composition and from toxic blood-borne substances. Although the endothelium provides the barrier properties of the BBB, it is the local brain microenvironment that elicits the unique phenotype. Vascular smooth muscle cells line precapillary arterioles; pericytes share a basement membrane with capillary endothelial cells; astrocytes ensheath the microvessels; and nerve terminals contact the endothelium. Together with the endothelium, these perivascular cell types constitute the so-called neurovascular unit (NVU).

As a result of BBB barrier properties, non-invasive delivery of small molecule pharmaceuticals and biopharmaceuticals (protein pharmaceuticals) to the brain is limited. Unless a molecule satisfies the dual criteria of having a small molecular size of less than 600 daltons and a high degree of lipid solubility, it will not appreciably cross the BBB. Because of these constraints, greater than 98% of small molecule pharmaceuticals do not cross the BBB and no biopharmaceuticals can cross this barrier. We are focused on overcoming this barrier through the development of non-invasive delivery methods that target drugs to the brain for the treatment of neurological diseases.

Traditionally, the design of neuropharmaceuticals has been chemistry-driven and has relied on the manipulation of small molecule compounds to satisfy the size and lipid solubility requirements. However, molecular engineering techniques allow us to take a different approach and employ endogenous transport mechanisms present at the BBB as a means to shuttle drug cargo from the blood to the brain. These cellular transport systems can be targeted using the exquisite specificity of antibodies that are in turn linked to a drug payload that can include small molecule pharmaceuticals, biopharmaceuticals, or even DNA therapeutics. We are therefore interested in the discovery of novel transport systems and cognate antibody targeting molecules, and we design high throughput selections that serve this purpose. Along these lines, we are also working to optimize the process for producing large amounts of therapeutic antibodies and proteins to meet the eventual demands of clinical application.

We are also interested in developing in vitro models of the BBB that accurately mimic the in vivo characteristics of the BBB. An in vitro BBB model would permit the combinatorial screening of drug candidates and drug-targeting strategies, a process that is not amenable to an in vivo system. When the endothelial cells that make up the BBB are cultured in vitro, however, changes in gene and protein expression occur thereby altering the permeability characteristics and integrity of the in vitro model. We have investigated these changes using genomics and proteomics techniques in an attempt to understand how gene and protein expression must be modulated to yield properties representative of the in vivo BBB. We are working to leverage this information for the development of novel in vitro models that possess more in vivo-like qualities. To this end, we have recently deployed pluripotent stem cell technology to model the human BBB in health and disease.  In addition to being able to predict drug permeability at the BBB, we are using patient-derived induced pluripotent stem cell technology to study the NVU in brain disease and identify antibodies capable of brain drug delivery.

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