Nanotherapeutic strategies for the treatment of chronic Chagas Disease

Chagas disease (CD, American trypanosomiasis), caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a serious public health problem throughout the western hemisphere in need of new treatment strategies The parasite has broad tropism, capable of infecting nearly any nucleated cell and allowing formation of parasitic reservoirs (especially in adipose tissue) that create a chronic risk of parasite reactivation. Chronic Chagas cardiomyopathy (CCC) manifests in approximately 1/3rd of infected individuals and is the leading cause of infectious myocarditis in the world. A need therefore exists for a strategy to selectively and locally inhibit inflammation in heart tissue that does not interfere with systemic immunity and synergizes with current Chagas drug regimens. Of note, Nifurtimox and Benznidazole (Bz) have been the mainstay of T. cruzi infection treatment for decades, despite their often severe toxicity and lack of efficacy in the treatment of CCC. Thus, the objective of this proposal is the development and validation of nanotherapies engineered to address 3 key issues for treatment of the chronic phase of CD. 1) Treatment of CCC without impacting parasitemia or parasite reservoir stimulation. CCC is associated with a localized pro-inflammatory, often autoimmune, response in the heart that necessitates an anti-inflammatory treatment strategy. But such a regimen risks activation of T. cruzi tissue reservoirs by decreasing adaptive immunity against the parasite. Thus, anti-inflammatory or tolerogenic strategies are needed that work within the boundaries of this complex immunoregulatory environment to simultaneously reduce cardiomyopathy and parasitic burden. 2) Targeted elimination of parasite reservoirs within adipose tissue, which is the primary reservoir for the majority of T. cruzi strains. A customizable therapeutic platform is needed for the targeted elimination of specific reservoir locations supporting chronic infection. 3) Development of a novel thiophene-based nanotherapeutic to treat Bz-resistant T. cruzi. New therapeutics with lower toxicity and alternative antiparsistic mechanisms are needed as alternatives to Benznidazole and Nifurtimox. We will therefore optimize a novel nanotherapeutic using patient-derived T. cruzi strains. These objectives will be accomplished using a well-vetted, robust, and customizable nanocarrier drug delivery platform employed by the Scott Lab at the University of Virginia (UVA) with assistance from the Nakamura Lab, which has investigated Chagas disease biology for decades at the Universidade Estadual de Maringá (UEM) in Brazil, an endemic location with access to clinically relevant T. cruzi strains. The following 2 aims will be achieved. Aim 1: Validate a tolerogenic/antiparasitic combination nanotherapy to treat established CCC without T. cruzi reactivation. SubAim1: Determine efficacy of the combination nanotherapy in multiple T. cruzi strains. SubAim2: Enhance targeting of T. cruzi adipose tissue reservoirs. Aim 2: Optimize a novel thiophene-loaded nanocarriers using Bz-resistant T. cruzi strains and clinical isolates. Project Number: 1R01HL175874-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Evan Scott | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $666,319 | Activity Code: R01 | Study Section: Innovations in Nanosystems and Nanotechnology Study Section [INN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17587401A1