A targeted approach to treating toxoplasmosis, a parasitic disease, shows early promise in test-tube and animal studies, where it prevented the parasites from making selected proteins. When tested in newly infected mice, it reduced the number of viable parasites by more than 90 percent, researchers from the University of Chicago Medicine report in the Proceedings of the National Academy of Sciences.
This precisely focused therapy combines short strands of "antisense" nucleic acid-like material with a small peptide that can transport those strands through cell membranes and into parasites, where they disrupt genetic signals. A similar approach from a team at Yale, published in April, showed comparable promise as a treatment for the parasites that cause malaria.
"This was proof of concept," said study author Rima McLeod, MD, a toxoplasmosis expert and professor at the University of Chicago Medicine. "We were able to cross multiple membranes, to insert the antisense strands into parasites living within cells and prevent them from making several different proteins. We now think we can shut down any of this parasite's genes."
"This approach may even have a role in non-parasitic diseases," she added. It is currently being tested in drug-eluting stents, as a treatment for bacterial or viral infections, including Ebola, and in patients with Duchenne muscular dystrophy, where it can block production of the defective segment of a dysfunctional gene.
The parasite McLeod and colleagues focused on, Toxoplasma gondii, is "probably the most common parasitic infection in the world," she said. "It infects as many as one-third of all humans, about two billion people worldwide." T. gondii causes disease in those who have immature immune systems, particularly those infected in utero. It also can be devastating for those who are immune-compromised and when it causes eye disease.
"New medications are urgently needed," she said. The standard treatments can cause side effects and patients may become hypersensitive to them. There are no medicines that can eliminate certain latent stages of the parasite's life cycle. There is no vaccine for humans.
The new treatment consists of a phosphorodiamidate morpholine oligomer (PMO), a short DNA-like molecule that binds to messenger RNA, preventing it from being translated into protein. This is conjugated to a "transductive peptide," a small molecule that can ferry the PMO across cellular barriers. The combination is known as a PPMO. An earlier study from the McLeod lab showed that such transductive peptides could bring small molecules into the untreatable dormant phase of the parasite.
The researchers tested this system in infected cells in tissue culture and in live, recently infected mice. It was able to knock down production of several distinct proteins.
They first tested their PPMO against easily detectable biomarkers by inserting genes for yellow fluorescent protein and for luciferase, a protein responsible for fireflies' glow, into parasites. Then they exposed parasite-infested cells to low levels of a PPMO targeting one piece of those genes. This reduced yellow fluorescence or dimmed bioluminescence by 40 to 60 percent.