The parasite’s ability to penetrate the human brain and survive in a dormant state without reproducing made it a perfect candidate for the researchers’ novel approach.
By Pesach Benson, TPS
Offering hope to people suffering neurological diseases, Israeli researchers have engineered a parasite to produce and release therapeutic proteins into the human brain.
“One of the biggest challenges in treating neurological diseases is getting through the blood-brain barrier,” explained Tel Aviv University Prof. Oded Rechavi, who led the international study.
“It is very difficult to deliver drugs to the brain via the bloodstream, and this is especially true for large molecules such as proteins, the critical ‘machines’ that carry out many important functions inside the cell.”
The blood brain barrier is a highly selective and protective barrier of tightly-packed cells that separates the circulating blood from the brain and central nervous system.
This protects the brain from harmful substances in the blood while allowing in essential nutrients. However, the barrier’s selective nature also poses challenges for delivering therapeutic drugs to the brain.
Collaborating with Rechavi was Prof. Lilach Sheiner, an Israeli scientist and toxoplasma expert from Scotland’s University of Glasgow.
Their findings were recently published in the peer-reviewed journal Nature Microbiology.
The creative solution proposed by the study team utilizes the unicellular parasite Toxoplasma gondii, which is sometimes known as the “cat parasite.”
This parasite can infect a wide range of organisms but reproduces only in the guts of cats.
It is highly effective in infecting humans, with an estimated third of the global population having been infected at some point in their lives.
“Most people don’t even feel the infection or only experience mild flu-like symptoms,” Rechavi said.
“The parasite is, however, dangerous for people with immune failure due to conditions like AIDS, and for fetuses whose immune systems have not yet developed. This is why pregnant women are advised not to eat raw meat, which might contain the parasite, and to stay away from cats, which might deliver it through their feces. While a healthy immune system can rid the body of the parasite, it has only limited access to the brain, and the parasite remains there throughout the carrier’s lifetime.”
The parasite’s ability to penetrate the human brain and survive in a dormant state without reproducing made it a perfect candidate for the researchers’ novel approach: genetically engineering Toxoplasma gondii to secrete therapeutic proteins.
“The parasite has three distinct secretion systems, and we ‘hitched a ride’ on two of them,” explains Prof. Rechavi.
“We did not intervene with the first system, which secretes proteins outside the neurons. The second system ‘shoots’ a ‘harpoon’ into the neuron to enable penetration. Once inside, the parasite forms a kind of cyst in which it continues to secrete proteins permanently. We engineered the parasite’s DNA to make it produce and secrete the proteins we want, which have therapeutic potential.”
Sheiner added, “The parasite’s ability to pass through the [blood brain barrier] and communicate with the neurons, combined with our ability to engineer the parasite, generates a golden opportunity for solving the great therapeutic challenge of delivering medications to the brain,” adds Prof. Sheiner.
For their study, the team used transgenic model animals that were injected with parasites genetically engineered to produce and secrete proteins that travel into cell nuclei.
Several lines of evidence proved that the proteins had been delivered to the target area and remained active in the neurons’ nuclei.
One of these was particularly eye-catching: a protein that, delivered by the parasite, entered the nuclei and cut out specific DNA segments, causing the transgenic animals’ brains to glow in the dark.
This breakthrough can have far-reaching implications for a series of severe diseases.
In the present study, the researchers specifically demonstrated the delivery of a protein called MeCP2, whose deficiency is associated with Rett syndrome.
“This is a deadly syndrome caused by a deficiency in a single gene called MePC2 in brain cells, and our engineered Toxoplasma gondii was able to deliver it to the target cells,” says Prof. Rechavi.
“But this is just one example. There are many other diseases caused by deficiency or abnormal expression of a certain protein.”
To ensure the method’s safe and effective therapeutic implementation, for both drug delivery and genetic editing, a company named Epeius was established in collaboration with Ramot – the technology transfer company of Tel Aviv University, and with the University of Glasgow’s research and innovation services.