Cell- and Tissue-Specific Nanotherapeutics Against Arthritis Progression and Joint Pain
Abstract
As the most common form of arthritis, osteoarthritis (OA) affects approximately 13.9% of adults aged 25 years and older in the United States. It can be caused by physical trauma such as neuromusculoskeletal combat injuries, which is also classified as post-traumatic OA. OA progression causes joint tissue harm such as articular cartilage degradation and inflammation of the synovium (which lines the surfaces in a joint not lined by cartilage). During the disease progression, the body increases production of inflammation cytokines and matrix proteases (enzymes that break down proteins), which leads to cartilage degradation and joint pain. After many attempts to inhibit inflammatory cytokines or matrix proteases to hinder OA progression, no therapeutic has been clinically approved. Small molecule inhibitors of matrix proteases showed early promise, but they elicited severe side effects due to the lack of molecular specificity. Some peptides can reduce cytokine levels in synovial fluid, but they don’t target the diseased tissues and cells to have sufficient efficacy. Based on the current state of knowledge, an overarching challenge in OA treatment is how to improve efficacy and specificity of OA therapeutics. To overcome the challenge, we aim to design and develop Cell- And Tissue-Specific (CATS) nanoparticles that can selectively deliver therapeutic siRNA (a type of RNA that, because it interferes with the expression of specific genes, is sometimes called “silencing RNA”) into different joint tissues (cartilage and synovium) at different disease phases (acute or chronic) to maximize treatment outcomes. SiRNA is a Nobel Prize discovery that provides great therapeutic potential to effectively and specifically inhibit disease gene expression. Different from conventional drugs, therapeutic siRNA must be delivered into cells to achieve their function. When we were developing a novel DNA-mimicking nanoparticle for siRNA delivery, we serendipitously discovered that the sizes and surface charges of the nanoparticles can determine which joint tissue they can get into. Therefore, we will develop CATS nanoparticles to precisely target the joint’s diseased tissues and cells as a novel OA treatment. Our proposed research is highly innovative because: 1) all outcomes of this project can be translated into clinical use in the future. This study lays a solid foundation for an advanced OA therapeutic that can precisely target the diseased tissues and cells to optimize treatment outcomes and minimize side effects. 2) For the first time, we have established a nanoscale delivery vehicle that can selectively target specific joint tissues and cells. Conventional targeted delivery solely relies on linkage of a targeting molecule onto the delivery vehicle, while our proposed CATS system constitutes a major technical breakthrough that combines chemical (targeting molecules) and physical (size-selection) means to achieve a previously untenable degree of selectivity. 3) Our technology can also serve as a research tool to clarify the different roles of synovium and cartilage during different disease phases (acute or chronic). It may help to explain why cartilage degradation and joint pain do not always correlate in OA patients. The proposed work will have significant positive impact on development of highly effective and specific OA therapeutics, as well as improving our understanding of the roles of arthritis-related genes at different joint tissues during different disease phases. This project will also lay important groundwork and provide high-quality data for future research projects that could develop CATS nanoparticles that target bone or have other useful applications. OA caused by joint injury is prevalent in military personnel and veterans. This proposal directly addresses “Arthritis” in the FY20 PRMRP topic areas. It fits in 1) “Basic and translational research to identify treatments to mitigate and/or reverse osteoarthritis,” and 2) “R
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110274
Entities
People
- Yupeng Chen
Organizations
- United States Army
- University of Connecticut