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Tuesday, 20 Mar, 2018
Crossing the blood-brain barrier
The blood-brain barrier (BBB) is a selective membrane that separates the circulating system from the brain. While this barrier is responsible for protecting the brain from potentially harmful agents circulating in the blood, it also acts as an obstacle preventing the delivery of therapeutics and other important molecules to the brain. A team from Duke-NUS have discovered a protein that transports lipids across the BBB. Based on this research, two Duke-NUS start-up companies are in the process of commercialising this technology in different ways: first, as an improved nutritional formulation, and secondly as a novel way to deliver therapeutics to the brain.
A major scientific breakthrough – Mfsd2a transports fatty acids across the BBB
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is critical for brain development. In adults, DHA is produced by the liver or derived from food such as fish, while a developing foetus receives DHA from its mother. In all situations, DHA must be transported from the blood circulatory system, across the BBB and into the brain. Until recently, the DHA transport mechanism was a mystery. The Duke-NUS researchers cracked this puzzle when they discovered that a transporter protein called Mfsd2a, expressed at the BBB and blood-eye barrier, carries DHA to the brain.
The researchers found that mice without a functional Mfsd2a transporter protein had significantly smaller brains, exhibited memory and learning disabilities and showed high levels of anxiety. These are symptoms similar to those exhibited by mice starved of DHA in their diet. Furthermore, they discovered that Mfsd2a also transports DHA into a growing foetal brain and the adult brain in the chemical form of lysophosphatidlycholine (LPC). LPCs are produced mainly by the liver and found at high levels in the human blood circulatory system. The research showed that Mfsd2a is critical for the uptake of DHA and other long chain fatty acids. This research was published in the prestigious publication Nature in May 2014.
A better approach to parenteral nutrition
The discovery of the Mfsd2a transporter has important applications in nutrition, particularly gestational, infant and children’s nutrition. Pre-term babies, who are born before 33 gestational weeks, and low birth-weight babies, may not have received sufficient DHA during foetal development, which can subsequently result in impaired learning abilities and vision. Current nutritional formulations are not ideal because, even though they contain DHA, it is not in the LPC form, resulting in sub-optimal DHA absorption. Duke-NUS has licensed the technology to a start-up company Babynostics, which is developing a range of LPC-based nutritional supplements that can be better absorbed for improved brain and cognitive development in infants and young children.
Delivering therapeutics to the brain
The second application area is in the development of a drug delivery system that can effectively transport specific small molecule therapeutics to the brain via the Mfsd2a transporter. Current approaches to deliver drugs across the BBB are less than ideal as they pose high risk to patients, lack specificity for the BBB, and exhibit low efficacy. The team is working on novel LPC-based scaffolds that can be used to transport small molecule drugs across the BBB, as well as the blood-eye barrier. Such scaffolds can potentially form the basis of a drug delivery system for the targeted delivery of therapeutics to the brain and eye. This technology has been licensed to a Singapore-based drug discovery company – Travecta.