Modeling Neurological Disorders at the Blood Brain barrier (BBB)

The blood brain barrier (BBB) is a multicellular neurovascular unit (NVU) in which pericytes, astrocytes, and neurons directly interact with brain microvascular endothelial cells (BMECs). In turn, BMECs form a specialized transporter barrier created by tight junctions and polarized efflux pumps. This fine-tuned cellular architecture permits the blood-to-central nervous system (CNS) passage of crucial molecules while prohibiting the entry of deleterious factors and most drugs. Several neurological disorders involve BBB dysfunction, creating the need to understand BBB physiology and transport mechanisms in health and disease. Marked differences in BBB substrate specificity and transporter activity across species limit the relevance of animal models. Therefore, a human-relevant BBB model is crucial to study human disorders and for the discovery of new CNS permeable drugs.

Combining induced pluripotent stem cells (iPSC) and Organ-on-Chip technologies we developed a platform in which isogenic iPSC-derived brain microvascular endothelial-like cells (iBMECs), astrocytes and neurons mimic human BBB functionality. iBMECs form a bioengineered vessel-like structure on the Organ-Chip and human astrocytes, pericytes and neurons form direct cell-to-cell interactions that mimic functionality at the level of an organ. The BBB-Chip exhibits physiologically relevant barrier functions. Disease modeling of the rare psychomotor disability MCT8-deficiency suggests that impaired transport of thyroid hormone (TH) across the BBB underlie this disorder.

We therefore next pre-clinically tested the potential of BBB-targeted AAV9-based gene therapy in a mouse model of MCT8-deficiency. Intravenous delivery of AAV9-MCT8 at a juvenile age resulted in a nearly complete rescue of TH brain content and TH-induced gene expression, accompanied with long-term rescue of the psychomotor and cognitive impairments. These studies pave the way for a clinical trial in the near future.