Tumor-Targeting Lipid Nanoparticle-Based siRNA Therapy for TSC
Abstract
This proposal addresses the following area: Eradicating tumors associated with tuberous sclerosis complex (TSC) and TSC-associated lymphangioleiomyomatosis (LAM), including gaining a deeper mechanistic understanding of TSC signaling pathways. TSC is a rare disorder that cause benign tumors to grow in multiple organs. The manifestations of TSC in the lung (LAM) and kidney (angiomyolipomas) can be treated and controlled with rapamycin and its analogues (rapalogs), inhibitors of the mammalian target of rapamycin (mTOR). However, there is no cure, and tumors regrow after the stop of the treatment. Thus, there is an urgent need for better treatments to eliminate tumor. We took a cutting-edge technology that enables gene expression analysis at single cell level to better understand tumor cells, and found that a subset population of tumor cells gained a special cell state often associated with drug resistance in various malignant cancers. We further identified a key gene potentially mediating drug resistance, and provided evidence that targeting this gene significantly improved rapamycin efficacy and re-activated immune system, potentially leading to a complete response and a cure to TSC. Thus, we sought to use RNA medicine to provide a solution by delivering a small interfering RNA (siRNA) to inhibit the gene. siRNA is a double-stranded RNA molecule, interfering with the expression of specific genes and prevent translation into functional proteins. Theoretically, any gene can be targeted using siRNAs for therapeutic intervention. siRNA therapy represents one of most recent breakthroughs in medicine. The U.S. Food and Drug Administration (FDA) approval, in 2018 and 2019, of two siRNA-based therapies (Patisiran and Givosiran) for genetic diseases represents a landmark for RNA medicine. One of advantage of siRNA therapy is its long-lasting therapeutic effect. For instance, twice-yearly administration of siRNA therapeutics has been shown sufficient to achieve optimal therapeutic effect, an unprecedent achievement in the pharmaceutical history. The biggest barrier to siRNA medicine is delivering siRNA molecules specifically into target organ and cell type. In collaboration with experts in nanotechnology, we have developed a biodegradable nanoparticle formula that specifically targets TSC-deficient tumor cells in vivo. Nanoparticles are between 1 and 100 nm in diameter. Nanoparticles are safe and often used in personal care products (to help ingredients penetrate the skin) and are a key emerging methodology for tumor-targeted drug delivery. In contrast to conventional systemic administration, nanoparticle delivery can be customized to target specific tissues or cell types, thereby minimizing side effects. Our preliminary data showed high efficiency of tumor cell-targeting nanoparticle in delivering siRNA therapeutics in vitro, which significantly enhanced rapamycin treatment in preventing tumor cell proliferation. The major goal of this project is to develop tumor cell-targeting nanoparticle-enabled siRNA therapy for TSC and determine whether siRNA therapy can enhance rapamycin treatment to eliminate tumor cells for a potential cure. The key translational delivery of the project is a transformative siRNA therapy strategy for TSC. We will also use state-of-the-art single cell analyses and multiomics analyses to identify molecular biomarkers of response to these treatments. The nanoparticle used in this project belong to the material category approved by FDA in 2018 for Patisiran (siRNA nanomedicine) and thus holds promise for rapid clinical translation. The clinical outcome of this study is an entirely novel therapeutic paradigm with the potential to re-normalize tumors associated with TSC and TSC-associated LAM with durable effect and complete response. The benefit of this project will extend far beyond the work proposed here, since nanoparticles can be used to deliver many different treatment cargos directly to tumo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210441
Entities
People
- Yan Tang
Organizations
- United States Army