ENGINEERING BRAIN PARASITES FOR DELIVERY OF THERAPEUTIC PROTEINS
Delivery of therapeutics across the blood brain barrier, and into neurons, is a major challenge that hinders the translation of new discoveries into therapy for neurological disorders. To tackle this we developed a novel synthetic biology solution to this problem: We engineered Toxoplasma gondii which evolved to migrate into the CNS and secrete proteins into cells, to deliver therapeutics proteins into neurons. In immuno-competent individuals, chronic Toxoplasma infections are highly common and harmless. In fact, it is estimated that a third of the world population is chronically infected with the parasite.
In the manuscript (see the pre-print “Engineering Brain Parasites for Intracellular Delivery of Therapeutic Proteins”), we describe the development of engineered T. gondii that secrete therapeutic proteins for various human neurological disorders. We hijacked two different secretion systems used by the parasite, one for transient protein delivery and the other for constitutive protein delivery, by engineering fusion proteins that localize to the two secretory organelles. We found that these strategies are efficient in achieving intracellular targeting in different mammalian cells including neurons. The unique behavior of this parasite which migrates specifically to the brain, uses multiple specialized secretion systems, and persists asymptomatically throughout life, highlight Toxoplasma as an excellent vector for protein delivery for untreatable neurological diseases.
Artwork by Dror Cohen.