From personalized BBB-on-Chip to pre-clinical BBB-targeted gene therapy for MCT8-deficiency

The blood brain barrier (BBB) is a multicellular neurovascular unit with fine-tuned cellular architecture that permits the blood-to-central nervous system (CNS) passage of crucial molecules while prohibiting the entry of deleterious factors and most drugs. Since BBB dysfunction contributes to neurological disorders and species differences limit animal model relevance, a human-specific BBB model is essential for studying disease mechanisms and developing 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.