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RNA-Based Therapy for Cryptosporidium parvum Infection: Proof-of-Concept Studies
A Castellanos-Gonzalez1, A Sadiqova1, J Ortega-Mendez1
1Department of Internal Medicine, Infectious Diseases Division, University of Texas Medical Branch, Galveston, Texas, USA.
Insights
Novel RNA therapies show promise against Cryptosporidium, a major cause of childhood diarrhea. Single-stranded RNA/Argonaute complexes effectively reduced parasite levels in lab and animal models, offering a potential new treatment for cryptosporidiosis.
Area of Science:
- Parasitology
- Molecular Biology
- RNA Therapeutics
Background:
- Cryptosporidium infection causes severe diarrhea in children, leading to significant mortality.
- Current treatment, nitazoxanide, has limited efficacy, especially in vulnerable populations.
- There is an urgent need for alternative therapies against Cryptosporidium.
Purpose of the Study:
- To evaluate the anticryptosporidial activity of single-stranded RNA (ssRNA)/Argonaute (Ago) complexes.
- To investigate the silencing of Cryptosporidium parvum nucleoside diphosphate kinase (NDK) using this novel RNA interference approach.
- To establish proof-of-concept for ssRNA/Ago complexes as a potential treatment for cryptosporidiosis.
Main Methods:
- Development of ssRNA/Ago complexes targeting essential genes in Cryptosporidium.
- In vitro studies using infected cell cultures to assess parasite burden reduction.
- In vivo studies in mouse models, including oral delivery of lipid nanoparticle-encapsulated complexes and assessment of oocyst shedding.
Main Results:
- A 3-day treatment with anti-sense NDK ssRNA/Ago complexes reduced parasite burden by approximately 98% in infected cells.
- ssRNA/Ago complexes encapsulated in lipid nanoparticles were successfully delivered to intestinal epithelial cells in mice.
- Treatment with NDK ssRNA/Ago complexes significantly reduced oocyst shedding in a cryptosporidiosis-mouse model.
Conclusions:
- Antisense RNA-based therapy using ssRNA/Ago complexes demonstrates significant anticryptosporidial activity.
- This approach shows potential for effective delivery to intestinal cells and reduction of parasite shedding in vivo.
- ssRNA/Ago complexes represent a promising alternative therapeutic strategy for cryptosporidiosis treatment.
Abstract:
Cryptosporidium is a leading cause of moderate-to-severe diarrhea in children, which is one of the major causes of death in children under 5 years old. Nitazoxanide is the only FDA-approved treatment for cryptosporidiosis. However, it has limited efficacy in immunosuppressed patients and malnourished children. Therefore, it is urgent to develop novel therapies against this parasite. RNA interference-mediated therapies are emerging as novel approaches for the treatment of infectious diseases. We have developed a novel method to silence essential genes in Cryptosporidium using single-stranded RNA (ssRNA)/Argonaute (Ago) complexes. In this work we conducted proof-of-concept studies to test the anticryptosporidial activity of these complexes by silencing Cryptosporidium parvum nucleoside diphosphate kinase (NDK) using in vitro and in vivo models. We demonstrated that a 3-day treatment with anti-sense NDK ssRNA/Ago decreased parasite burden by ~98% on infected cells. In vivo studies showed that ssRNA/Ago complexes encapsulated in lipid nanoparticles can be delivered onto intestinal epithelial cells of mice treated orally. In addition a cryptosporidiosis-mouse model showed that treatment with NDK ssRNA/Ago complexes reduced oocyst shedding in 4/5 SCID/beige mice during the acute phase of the infection. Our findings highlight the potential use of antisense RNA-based therapy as an alternative approach to cryptosporidiosis treatment.
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