An international team of neurobiologists has developed a way to use a single-celled parasite Toxoplasma Gondii to deliver therapeutic proteins directly into brain cells. In this study published in Nature Microbiology, the researchers addressed the challenge of the brain’s selective permeability, which restricts treatment options for neurological conditions.
Pills are a convenient way to administer medicine, with small chemical drugs like aspirin easily absorbed into the bloodstream from the gut. However, biologic drugs, such as semaglutide, are large and complex, making them prone to degradation in the stomach and unable to cross the intestinal wall. Moreover, all drugs, particularly biologics, struggle to penetrate the brain due to the blood-brain barrier, which protects the brain by blocking harmful substances from reaching neurons.
Toxoplasma parasites can infect all animals, including humans, through routes such as ingesting spores from infected cat stool or consuming contaminated meat or water. In healthy individuals, Toxoplasmosis typically causes mild symptoms but can be severe for those with weakened immune systems or pregnant women. Unlike most pathogens, Toxoplasma can cross the blood-brain barrier and invade brain cells, where it releases proteins that alter gene expression. This may contribute to behavioral changes observed in infected animals and humans.
In this study, researchers successfully engineered Toxoplasma parasites to secrete a hybrid protein that combines one of its own secreted proteins with MeCP2, a protein involved in regulating gene activity in the brain. This hybrid protein was then miraculously delivered into neurons both in vitro and in the brains of infected mice. Since a genetic deficiency in MECP2 causes Rett syndrome, which is currently being targeted in gene therapy trials using viruses, Toxoplasma’s ability to deliver MeCP2 could provide a new treatment approach for Rett syndrome and potentially other neurological disorders like Alzheimer’s and Parkinson’s disease.
Utilizing Toxoplasma for therapeutic purposes is challenging due to its potential to cause severe, incurable infections. Nonetheless, since approximately one-third of people worldwide harbor Toxoplasma in their brains without noticeable problems, the concept of using it for drug delivery becomes more feasible. Additionally, by engineering benign strains of the parasite, it may be possible to deliver essential proteins effectively while avoiding harm to the brain and other vital organs.
Extracted from the essay “Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons” Written by Shahar Bracha et al
Published on Nature Microbiology July 2024
Source: Shahar Bracha, Hannah J. Johnson, Nicole A. Pranckevicius, Francesca Catto, Athena E. Economides, Sergey Litvinov, Karoliina Hassi, Marco Tullio Rigoli, Cristina Cheroni, et al “Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons” – July 2024