Infection by Trypanosoma brucei brucei

Scientists discovered that 1) the wasting response to T. brucei infection in mice occurs in two phases, each regulated by different immune cells and 2) fat loss did not benefit the fight against infection, but muscle loss did. The findings inform the development of more effective therapeutics that spare people from wasting and increase our understanding of how wasting influences survival and morbidity across infections, cancers, chronic illnesses, and more. Although infections can present with many different symptoms, one common symptom is the loss of fat and muscle, a process called wasting. Salk scientists wanted to know whether wasting was beneficial in fighting infections. Researchers in Professor Janelle Ayres' lab discovered the wasting response to T. brucei infection in mice occurs in two phases, each regulated by different immune cells. While fat loss did not benefit the fight against infection, muscle loss did -- a surprising clue that some wasting may help manage illness. The findings, published in Cell Reports on July 24, 2023, can inform the development of more effective therapeutics that spare people from wasting and increase our understanding of how wasting influences survival and morbidity across infections, cancers, chronic illnesses, and more. "We oftenmake assumptions that conditions like wasting are bad, since they often coincide with higher mortality rates," says senior author Ayres, Salk Institute Legacy Chair and head of the Molecular and Systems Physiology Laboratory. "But if instead we ask, what is the purpose of wasting? We can find surprising and insightful answers that can help us understand the human response to infection and how we can optimize that response." Defending the body from an invader requires a lot of energy. Prior studies suggested this immune-related energy consumption had the unfortunate consequence of wasting. But Ayres and team were curious to know whether wasting could be beneficial and not just a side effect. Specialized immune cells called T cells are slow to respond to infections, but when they do respond, they adapt to fight the particular infection. Ayres was interested to know whether it was these T cells causing wasting. If T cells are responsible for the condition, that would indicate wasting is not simply an unproductive side effect of energy-hungry immune cells. The cells of interest are called CD4+ and CD8+ T cells. CD4+ T cells lead the fight against infection and can promote the activity of CD8+ T cells, which can kill invaders and cancerous cells. The two T cell types often work together, so the researchers hypothesized their role in wasting may be a cooperative effort, too. To work out the relationship between CD4+ and CD8+ T cells and wasting, the researchers turned to the parasite T. brucei. Because T. brucei lives in fat and can block the adaptive immune response -- which includes T cells -- it was a perfect model infection for their questions about fat wasting and how T cells mediate that process. The team investigated 1) the role of CD4+ and CD8+ T cells during T. brucei infection and 2) how removing CD4+ and CD8+ T cells changed the longevity, mortality rates, parasite symptoms, and amount of parasite present in infected mice. The researchers found that CD4+ T cells acted first and initiated the process of fat wasting. Afterward, but completely independently of the fat wasting, CD8+ T cells initiated the process of muscle wasting. The CD4+ T cell-induced fat wasting had no impact on the ability for the mice to fight T. brucei or to survive infection. The CD8+ T cell-induced muscle wasting, however, contrary to the traditional assumptions about wasting, helped the mice fight T. brucei and survive the infection. "Our discoveries were so surprising that there were times I wondered if we did something wrong," says first author Samuel Redford, a current visiting researcher and former graduate student in Ayres' lab. "We had striking results that mice with fully functioning immune systems and mice without CD4+ T cells lived the same amount of time -- meaning, those CD4+ T cells and the fat wasting they caused were completely disposable in fighting the parasite. And beyond that, we found that normally cooperative T cell subtypes were working totally independently of one another." The findings illustrate the important role of immune cells in both fat and muscle wasting and the necessity to understand the function of such responses to inform therapeutic interventions. "We can learn so much about our immune systems by looking at the environments and infections we have co-evolved with," says Ayres. "While T. brucei is an interesting and important case, what is exciting is extrapolating our findings to understand, treat, and overcome any disease that involves immune-mediated wasting -- parasites, tumors, chronic illnesses, and so much more." In the future, the team will examine the T cell mechanism in other mammals and eventually humans. They also want to explore in more detail why muscle wasting is occurring and why CD4+ and CD8+ T cells play these distinct roles. Other authors include Siva Karthik Varanasi, Karina Sanchez, and Natalia Thorup of Salk. The work was supported by the National Institutes of Health (DPI AI144249, R01AI14929, NCI CCSG: P30 CA014195).

HAT-301 is the Pivotal Efficacy Study to Support Upcoming NDA Filing Top Line Results Planned for Release in July 2023 TARRYTOWN, NY, June 01, 2023 (GLOBE NEWSWIRE) -- via NewMediaWire – PaxMedica, Inc. (Nasdaq: PXMD), a clinical stage biopharmaceutical company focusing on the development of novel anti-purinergic drug therapies (APT) for the treatment of Autism Spectrum Disorder (ASD), and other serious conditions with intractable neurologic symptoms, today announced that the eligibility review and final enrollment for the company’s Real World Evidence study (HAT-301) has been completed. Patient eligibility was assessed for inclusion by an Independent Study Adjudication Committee which included a total of three subject matter expert medical reviewers. The comparative arms for this pivotal Phase 3 Real World Evidence study included: A total of 145 patients treated with suramin in Uganda and Malawi between 2000 – 2022, andA total of 204 natural history cases from patients in Uganda and Malawi between 1900-1910, prior to the availability of suramin. The HAT-301 study is the first and only retrospective clinical study of suramin in the treatment of Rhodesian African Sleeping Sickness, also known as Stage 1 Trypanosoma Brucei Rhodesiense Human African Trypanosomiasis (TBR HAT), a rare and universally fatal infectious disease. Suramin has been the standard of care for treating TBR HAT for many decades, solely based on empirical evidence derived during mass epidemics of TBR HAT. The official database lock for HAT-301 will occur in June 2023, with top-line data for this study expected to be available in July 2023, and pave the way for filing an NDA for the use of PAX-101 in TBR HAT in 2024. If approved, suramin will be the first drug indicated for the treatment of TBR HAT in the United States and would possibly qualify PaxMedica to receive a Priority Review Voucher (PRV) under section 524 of the Food, Drug, and Cosmetics Act (FD&C Act). A PRV, once granted, is an independently valued asset (see GAO report 20-251), granted to a sponsor company after NDA approval and, according to section b)2) of the act, can be sold by that sponsor to any biopharmaceutical company to obtain FDA priority review in a future filing of any NDA. Howard Weisman, Chief Executive Officer of PaxMedica, commented, “Database lock for the HAT-301 study is a significant threshold event for PAX-101. With this achievement, PaxMedica has completed a critical step in filing for potential U.S. market approval for this important, life-saving treatment. The opportunity to raise significant non-dilutive funding, as a result of our potential successful participation in the Neglected Rare Tropical Disease Program through receipt of a PRV, may enable future large-scale trials of PAX-101 in Autism, and other important conditions, in the very near future. This remains central to our strategy to build and support sustainable long term shareholder value.” About the Phase 3 HAT-301 Trial Launched in November 2022, the Phase 3 HAT-301 trial is a pivotal, retrospective, controlled analysis of suramin for the treatment of the rare and fatal tropical disease, TBR HAT. The study has been underway at multiple primary HAT treatment sites in Uganda and Malawi using exclusively licensed, retrospective clinical data that is being reviewed, and compared with a natural history-controlled dataset comprised of exclusively licensed source data. The primary objective of the study is to demonstrate that the standard of care treatment using suramin, as currently practiced in Uganda and Malawi, leads to better clinical outcomes in patients with Stage 1 Trypanosoma Brucei Rhodesiense Human African Trypanosomiasis than observed in an untreated natural history cohort, that had documented illness prior to availability of suramin. The World Health Organization lists suramin, discovered in 1916, and found to be effective against Stage 1 Trypanosoma Brucei Rhodesiense Human African Trypanosomiasis since at least 1920, as a standard of care for Trypanosoma b. Rhodesiense. About PaxMedica PaxMedica is a clinical stage biopharmaceutical company focusing on the development of anti-purinergic drug therapies (“APT”) for the treatment of disorders with intractable neurologic symptoms, ranging from neurodevelopmental disorders, including Autism Spectrum Disorder (“ASD”), to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (“ME/CFS”), a debilitating physical and cognitive disorder believed to be viral in origin and now with rising incidence globally due to the long term effects of SARS-CoV-2 (“COVID-19”). One of PaxMedica’s primary points of focus is the development and testing of its lead program, PAX-101, an intravenous formulation of suramin, in the treatment of ASD and the advancement of the clinical understanding of using that agent against other disorders such as ME/CFS and Long COVID-19 Syndrome, a clinical diagnosis in individuals who have been previously infected with COVID-19. For more information, visit www.paxmedica.com. 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