Center for Tropical and Emerging Global Diseases
University of Georgia
Rick Tarleton, Regents’ Professor in Franklin College‘s Department of Cellular Biology and member of CTEGD, is the featured guest on this episode of People, Parasites, and Plagues. Listen as he discusses his work with Trypanosoma cruzi and Chagas Disease, what transmission looks like here in the U.S., and the important research being done in this area.
Trypanosoma cruzi, the protozoan parasite and cause of Chagas disease, is widely distributed in many vertebrate and triatomine species throughout North, Central, and South America. Variations in housing quality largely determines human infection risk in the Americas. However, the southern U.S. contains widespread, infected triatomine vectors and captive species and domesticated animals with active T. cruzi infection or at high risk of becoming infected and developing Chagas disease. There is a critical need for better detection and intervention strategies, principally focused on human infection throughout the Americas, but mainly in the U.S., for high-value dogs employed in government and other work. In addition to this economic impact, the concentration of largely unavoidable T. cruzi infections in U.S. dogs provides an incomparable opportunity to answer questions related to T. cruzi infection and Chagas disease that are impossible or unethical to address in humans. As the course of T. cruzi infection and Chagas disease, the immune response to infection, and the response to therapeutics are highly similar across the range of mammalian host species, information obtained from studies in other species can directly inform researchers on how to best detect, manage, and treat T. cruzi infection and Chagas disease in humans.
Rick L. Tarleton, Ashley B. Saunders, Bruno Lococo, Maria Gabriela Alvarez Gianni, Susana Laucella, Carolyn L. Hodo, Gregory K. Wilkerson, Sarah A. Hamer. Zoonoses. 2024. Vol. 4(1). DOI: 10.15212/ZOONOSES-2024-0005
Trypanosoma cruzi infection in dogs can cause heart failure and sudden death with few treatment options available. A litter of 4 dogs living in a T cruzi endemic area were randomized to prophylaxis and nonprophylaxis groups as part of a study evaluating a modified benznidazole dosing regimen administered twice weekly to prevent T cruzi infection during a vector transmission season. The 2 dogs that received prophylaxis remained healthy without T cruzi infection or cardiac disease for >2 years. One dog that did not receive prophylaxis died unexpectedly with acute T cruzi-induced pancarditis, and the second dog tested positive for T cruzi and developed complex arrhythmias with markedly increased cardiac troponin I and improved with a higher benznidazole treatment dose. Although the small sample size precludes definitive conclusions, we describe the potential clinical benefit of prophylactic and early treatment with modified benznidazole dosing regimens for dogs with T cruzi infection.
Sukjung Lim, Stephanie Collins, Sarah A Hamer, Rick L Tarleton, Ashley B Saunders. J Vet Intern Med. 2024 Mar 18. doi: 10.1111/jvim.17028.
Rick Tarleton was recently interviewed for the Drug Discovery News podcast. Listen as he talks about his research into new drug treatments for Chagas disease.
A written transcript is available on DDN’s website.
Rick Tarleton, along with Drew Etheridge‘s lab, was featured in a KFF Health News story about Chagas disease that has been picked up by a number of media outlets.
KFF Health News (Spanish translation)
The Chagas field has gone >50 years without tangible progress toward new therapies. My colleagues and I have recently reported on a benzoxaborole compound that achieves consistent parasitological cure in experimentally infected mice and in naturally infected non-human primates (NHPs). While these results do not assure success in human clinical trials, they significantly de-risk this process and form a strong justification for such trials. Highly effective drug discovery depends on a solid understanding of host and parasite biology and excellent knowledge in designing and validating chemical entities. This opinion piece seeks to provide perspectives on the process that led to the discovery of AN15368, with the hope that this will facilitate the discovery of additional clinical candidates for Chagas disease.
Rick L. Tarleton. Trends Parasitol. 2023 Jun;39(6):423-431. doi: 10.1016/j.pt.2023.03.015.
Background: A drawback in the treatment of chronic Chagas disease (American trypanosomiasis) is the long time required to achieve complete loss of serological reactivity, the standard for determining treatment efficacy.
Methods: Antibody-secreting and memory B cells specific for Trypanosoma cruzi and their degree of differentiation were evaluated in adult and pediatric subjects with chronic Chagas disease prior to and after etiological treatment.
Results: Trypanosoma cruzi-specific antibody-secreting cells disappeared from the circulation in benznidazole or nifurtimox-treated subjects with declining parasite-specific antibody levels posttreatment, whereas B cells in most subjects with unaltered antibody levels were low prior to treatment and did not change after treatment. The timing of the decay in parasite-specific antibody-secreting B cells was similar to that in parasite-specific antibodies as measured by a Luminex-based assay, but preceded the decay in antibody levels detected by conventional serology. The phenotype of total B cells returned to a non-infection profile after successful treatment.
Conclusions: T. cruzi-specific antibodies in the circulation of chronically T. cruzi-infected subjects likely derive from both antigen-driven plasmablasts, that disappear following successful treatment, and long-lived plasma cells that persist and account for the low frequency and long course to complete seronegative conversion in successfully treated subjects.
G Cesar, M A Natale, M C Albareda, M G Alvarez, B Lococo, Ana María De Rissio, Marisa Fernandez, M Castro Eiro, G Bertocchi, B E White, F Zabaleta, R Viotti, R L Tarleton, S A Laucella.J Infect Dis. 2022 Dec 26;jiac495. doi: 10.1093/infdis/jiac495. Online ahead of print.
Human clinical trials are expensive, and when they fail, they create the impression that a problem is intractable, thus depressing interest in future attempts. For neglected tropical diseases, where there are likely limited numbers of “shots on goal”, such failures need to be assiduously avoided. Chagas disease drug discovery efforts have experienced more than its share of human clinical trial failures. Here Here are some guidelines, many specific for Chagas, but some which might also have application for other neglected tropical diseases. Chagas disease has major challenges (e.g., the lack of a definitive test of cure) but also has outstanding advantages, among these the unmatched multi-species natural infection systems that can be exploited to de-risk compounds before human trials. Fully utilizing these advantages while frankly acknowledging and addressing the challenges should bring better options to patients, sooner.
Rick Tarleton. Clin Infect Dis. 2022 Nov 14;ciac884. doi: 10.1093/cid/ciac884. Online ahead of print.
Researchers from the University of Georgia have discovered a potential treatment for Chagas disease, marking the first medication with promise to successfully and safely target the parasitic infection in more than 50 years.
Human clinical trials of the drug, an antiparasitic compound known as AN15368, will hopefully begin in the next few years.
“I’m very optimistic,” said Rick Tarleton, corresponding author of the study and a UGA Athletic Association Distinguished Professor in the Franklin College of Arts and Sciences and member of the Center for Tropical and Emerging Global Diseases. “I think it has a really strong chance of being a real solution, not just a stand-in for something that works better than the drugs we currently have.”
The new drug works by targeting the parasite that causes the disease, Trypanosoma cruzi, also known as T. cruzi.
Nearly all people infected with the parasite experience flu-like symptoms such as fever, headaches and vomiting. However, after their immune response kicks in, their symptoms may subside.
But for 30% to 40% of patients, the infection can result in severe heart damage that can be both debilitating and life-threatening.
Published in Nature Microbiology, the study found the new medication was 100% effective in curing mice, as well as non-human primates that were naturally infected by the parasite at a research facility in Texas. The animals also experienced no significant side effects from exposure to the drug.
Over the past several decades, previous treatment candidates went straight from experimental infections in mice to human clinical trials, where they failed to cure the infection. The new drug’s efficacy in non-human primates bodes well for how it will perform in humans.
“We’ve got something that is as close to effective as it can be in what is as close to a human as it could be, and there aren’t any side effects. That really de-risks it by a lot going into humans,” Tarleton said. “It doesn’t make it fail-safe, but it moves it much further along.”
T. cruzi is carried by blood-sucking insects known as kissing bugs. The insects can be found throughout North, Central and South America.
In addition to a nasty bite, the creatures carry the T. cruzi parasite, which is transmitted through their fecal matter. Victims can become infected when they unknowingly rub the insect’s feces into their eyes, nose or an open wound.
The infection may also be transmitted through organ transplants, from a pregnant person to their fetus or through contaminated food. However, infections from these pathways are less common.
The go-to medications used to treat Chagas aren’t terrible, Tarleton said, but they’re not ideal. They can pack some serious side effects and they’re not reliably effective, but they’re currently the only treatment option.
Patients also have to take the drugs for two months. And even the common but mild side effects like headache or nausea get old after a few weeks. As a result, about one in five people being treated for the disease stop taking their medications before they have a chance to cure the infection.
“Plus they have variable efficacy, and it’s not predictable,” Tarleton said. “I think most physicians in Latin America have to say, ‘We have a drug. It’s going to make you feel bad, and two months later after we finish it, we’re not really going to be able to tell you if it worked or not.’
“It’s really not a good inducement to take the medication.”
Tens of millions of people across the Americas are infected with the parasite that causes Chagas disease. But it doesn’t get much media attention.
It’s most common in Latin American countries, particularly in low-income areas where housing isn’t ideal. Some of the countries with the highest rates of the disease include Bolivia, Venezuela, Argentina, Chile, Mexico and Brazil.
In homes with thatched roofs, mud walls or inadequate protection from the elements, kissing bugs thrive, making infection more likely.
The Centers for Disease Control and Prevention estimates around 300,000 people infected with the parasite currently live in the U.S. But because the condition isn’t a huge threat in places with good housing options, Chagas disease treatment and prevention doesn’t get much research funding.
There is growing concern about the T. cruzi infection rate among outdoor pets in the U.S., however. Working dogs and other pets that spend extended periods of time outside are contracting the parasite at an alarming rate.
“There are areas where the infection rates are 20% to 30% new infections per year,” Tarleton said. “Those tend to be severe infections where the dogs either die or develop a disease that makes them unable to work.”
Tarleton hopes to partner with veterinary pharmaceutical companies in the future to create a drug to treat the infection in pets as a means of funding diagnostics and medication purchases in Latin America.
For the present study, Tarleton partnered with colleagues at Anacor Pharmaceuticals, Texas A&M University, the University of Texas, the University of Kansas and Pfizer. Angel Padilla, Wei Wang, Dylan Orr, Brooke White, Arlene George and Huifeng Shen from UGA’s Center for Tropical and Emerging Global Diseases and the Department of Cellular Biology are co-authors on the paper.
Story by Leigh Beeson. It was first published at https://news.uga.edu/researchers-discover-potential-treatment-for-chagas-disease/
Rick Tarleton and colleagues recently published their new study, “Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates” in Nature Microbiology. Check out these news stories about the study.
Behind the paper: New Hope for Treatment of a Very Neglected, Neglected Tropical Disease (Nature Microbiology)
Possible new treatment identified for neglected tropical disease (Science.org)
Researchers discover potential treatment for Chagas disease (Mirage News)
Researchers discover potential treatment for Chagas disease (Science Daily)
Researchers discover potential treatment for Chagas disease (Medical Xpress)
Chagas disease potential treatment: ‘I think it has a really strong chance of being a real solution’ (Outbreak News Today)
Promising New Drug May Effectively Treat Chagas Disease (Technology Networks)
Researchers discover potential treatment for Chagas disease (Newswise)
Potential Treatment for Chagas Disease (Labroots)
New Compound Shows Promise for Treating Chagas Disease (GEN)
Could Researchers Have Discovered a Chagas Disease Treatment? (PatientWorthy)
Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease.
Angel M. Padilla, Wei Wang, Tsutomu Akama, David S. Carter, Eric Easom, Yvonne Freund, Jason S. Halladay, Yang Liu, Sarah A. Hamer, Carolyn L. Hodo, Gregory K. Wilkerson, Dylan Orr, Brooke White, Arlene George, Huifeng Shen, Yiru Jin, Michael Zhuo Wang, Susanna Tse, Robert T. Jacobs & Rick L. Tarleton. Nat Microbiol (2022). https://doi.org/10.1038/s41564-022-01211-y
