Featured Research

from universities, journals, and other organizations

Antisense approach promising for treatment of parasitic infections

Date:
August 13, 2012
Source:
University of Chicago Medical Center
Summary:
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.

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.

Next, they tested its ability to block production of an enzyme, dihydrofolate reductase (DHFR), that the parasite needs to make folate and to replicate. After 48 hours, DHFR production of intracellular parasites was markedly reduced. Antisense oligomers targeting another enzyme and factors that direct the activity of many genes, called "transcription factors," associated with parasite replication, "also were successful," the authors note, "reducing parasite replication."

When they tested the anti-DHFR PPMO in newly infected mice, the results were dramatic. Within 96 hours, treatment reduced the number of parasites by 83 percent to 97 percent, depending on the measurement technique.

This approach is "paradigm shifting," McLeod said. "It has the potential to abrogate any molecular target and underscores the variety of diseases for which such an approach might apply."

The technology still has a few problems, she said. These PPMOs have a narrow therapeutic index; they can be toxic at a little more than the lowest effective dose. And we have not yet developed a way to eradicate latent stages of T. gondii, which can lie dormant in retina or brain cells for years, but such studies are underway. The researchers hope to use this technique to awaken dormant parasites, and then use drugs or PPMOs that target replicating parasites to kill them or eliminate both active and dormant parasite stages by targeting their plant-like transcription factors and other proteins unique to the parasites that humans don't have.

Much of the credit for developing and testing this system should go to the study's lead author, McLeod said.

Bo-Shiun Lai, a 20-year-old rising fourth-year college student at the University of Chicago, stumbled into his research position in McLeod's laboratory but adapted quickly. "Although it was difficult at the outset," he said, "everyone in the lab helped me develop the project and hone my laboratory techniques along the way."

It paid off. He completed his senior thesis as a junior, with honors, and will be applying for PhD programs.

This study was funded by the National Institutes of Health and gifts from the Mann and Cornwell, Taub, Rooney-Alden, Engel, Pritzker, Harris, Zucker, Morel and Mussilami families. Additional authors include Kamal El Bissati, Ying Zhou, Ernest Mui and Alina Fomovska of the University of Chicago, and William Witola, now at Tuskeegee University in Alabama.


Story Source:

The above story is based on materials provided by University of Chicago Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Bo-Shiun Lai, William H. Witola, Kamal El Bissati, Ying Zhou, Ernest Mui, Alina Fomovska, and Rima McLeod. Molecular target validation, antimicrobial delivery, and potential treatment of Toxoplasma gondii infections. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1208775109

Cite This Page:

University of Chicago Medical Center. "Antisense approach promising for treatment of parasitic infections." ScienceDaily. ScienceDaily, 13 August 2012. <www.sciencedaily.com/releases/2012/08/120813155638.htm>.
University of Chicago Medical Center. (2012, August 13). Antisense approach promising for treatment of parasitic infections. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2012/08/120813155638.htm
University of Chicago Medical Center. "Antisense approach promising for treatment of parasitic infections." ScienceDaily. www.sciencedaily.com/releases/2012/08/120813155638.htm (accessed September 21, 2014).

Share This



More Plants & Animals News

Sunday, September 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Raw: San Diego Zoo Welcomes Cheetah Cubs

Raw: San Diego Zoo Welcomes Cheetah Cubs

AP (Sep. 20, 2014) The San Diego Zoo has welcomed two Cheetah cubs to its Safari Park. The nearly three-week-old female cubs are being hand fed and are receiving around the clock care. (Sept. 20) Video provided by AP
Powered by NewsLook.com
Chocolate Museum Opens in Brussels

Chocolate Museum Opens in Brussels

AFP (Sep. 19, 2014) Considered a "national heritage" in Belgium, chocolate now has a new museum in Brussels. In a former chocolate factory, visitors to the permanent exhibition spaces, workshops and tastings can discover derivatives of the cocoa bean. Duration: 01:00 Video provided by AFP
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com
Jury Delivers Verdict in Salmonella Trial

Jury Delivers Verdict in Salmonella Trial

AP (Sep. 19, 2014) A federal jury has convicted three people in connection with an outbreak of salmonella poisoning five years ago that sickened hundreds of people and was linked to a number of deaths. (Sept. 19) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins