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Publicly released:
2024-07-30 01:00
International scientists have given a whole new meaning to the phrase ‘a game of cat and mouse’! They’ve engineered a parasite commonly found in cat faeces, Toxoplasma gondii, so that rather than causing a nasty condition called toxoplasmosis, it delivers beneficial drugs to the brains of mice. The brain is hard for drugs to reach because of a special barrier that protects it, but the parasite has ways around the usual defences as it travels from the gut into the brain, so the team decided to take advantage of it. They sneakily inserted two proteins used to treat a human brain and nerve condition called Rett syndrome into the parasite, and showed they were transferred into the brains of infected mice. They checked to see how much parasite was present outside the targeted delivery sites, finding just a few, and say the T. gondii infection did not appear to cause any inflammation in the rodents’ brains. Further research should test how effective and safe the approach might be in human patients, the researchers conclude.
Journal/conference: Nature Microbiology
Link to research (DOI): 10.1038/s41564-024-01750-6
Organisation/s: Massachusetts Institute of Technology, USA
Funder: The work was
supported by the Nadal Colton Applied Research Fund (O.R. and S.B.),
Basic Research grant from the International Rett Syndrome Foundation
(L.S., O.R., S.C. and S.B.), University of Glasgow Knowledge Exchange
fund (L.S.), National Institutes of Health award NS095994 (A.A.K.)
and T32AG061897 (H.J.J.), European Research Council Advanced
Grant No. 341117 (P.K.), Royal Society of Edinburgh Personal Research
Fellowship (L.S.), Adelis foundation grant no. 0604916191 (O.R.), Eric
and Wendy Schmidt Fund for Strategic Innovation Polymath Award
no. 0140001000 (O.R.) and support from the Morris Kahn foundation
(O.R.). The Wellcome Centre for Integrative Parasitology is supported
by core funding from the Wellcome Trust (104111) (L.S., D.W.). The UA
Tissue Acquisition and Cellular/Molecular Analysis Shared Resource,
UA Cancer Center is supported by NIH grant P30CA023074 (A.A.K.
and H.J.J.).
Media release
From: Springer Nature
Engineered parasite could deliver therapeutic proteinsA method to engineer the parasite Toxoplasma gondii to deliver therapeutic proteins to host neurons across the blood–brain barrier using a mouse model is reported in Nature Microbiology. The findings could enable the development of alternative approaches for therapeutic protein delivery.Proteins can be used as therapies or as tools to study biological processes. However, their delivery to target cells and tissues is complicated by their large size, interactions with the host immune system and the need to bypass different barriers, such as the blood–brain barrier. T. gondii is a parasite that naturally travels from the human gut to the central nervous system. Previous work has demonstrated that T. gondii can deliver proteins to host cells, but whether this parasite could be engineered to deliver multiple, large therapeutic proteins is unclear.Shahar Bracha and colleagues developed a strategy to use the two secretory organelles (specialised structures that perform jobs inside a cell) of T. gondii — the rhoptries and dense granules — to deliver proteins into host cells. They selected proteins located in the parasite’s organelles and fused them to different proteins that are known to treat human neurological conditions. The authors successfully demonstrated via laboratory experiments that the proteins could be delivered from both secretory organelles to neurons at the same time.As proof of concept, they show that a therapeutic protein, MeCP2, used to treat Rett syndrome (a rare neurological disorder that impacts brain development) could be delivered to neurons, bind target DNA and alter host gene expression in cells and in neuron and brain organoids. Bracha and colleagues also show that engineered T. gondii can deliver MeCP2 to neurons in mice with few parasites detected outside the target delivery site and no significant inflammation following delivery.The authors conclude that although the findings could enable new approaches for therapeutic protein delivery, further research is needed to understand the potential limitations, including efficacy and safety.
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