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1. β-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model.

Author

Nelson, Anna, Mancino, Chiara, Gao, Xueqin, Choe, Joshua, Chubb, Laura, Williams, Katherine, Czachor, Molly, Marcucio, Ralph, Taraballi, Francesca, Cooke, John, Huard, Johnny, Bahney, Chelsea, and Ehrhart, Nicole

Subjects
Canonical Wnt, Fracture healing, Gene therapy, Lipid nanoparticles, mRNA
Abstract

Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding β-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection, minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs. The generated β-cateninGOF mRNA encapsulated in SM-102 LNPs (SM-102-β-cateninGOF mRNA) showed bioactivity in vitro through upregulation of downstream canonical Wnt genes, axin2 and runx2. When testing SM-102-β-cateninGOF mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 μg concentration at 2 weeks post-fracture. μCT testing confirmed that SM-102-β-cateninGOF mRNA promoted bone formation in vivo, revealing significantly more bone volume over total volume in the 45 μg group. Thus, we generated a novel mRNA-based therapeutic encoding a β-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Published
2024

6. Heterologous mRNA-protein vaccination with Tc24 induces a robust cellular immune response against Trypanosoma cruzi, characterized by an increased level of polyfunctional CD8+ T-cells

Author

Poveda, Cristina, Leão, Ana Carolina, Mancino, Chiara, Taraballi, Francesca, Chen, Yi-Lin, Adhikari, Rakesh, Villar, Maria Jose, Kundu, Rakhi, Nguyen, Duc M., Versteeg, Leroy, Strych, Ulrich, Hotez, Peter J., Bottazzi, Maria Elena, Pollet, Jeroen, and Jones, Kathryn M.

Published
2023
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9. Harnessing RNA Technology to Advance Therapeutic Vaccine Antigens against Chagas Disease

Author

Mancino, Chiara, Pollet, Jeroen, Zinger, Assaf, Jones, Kathryn M., Villar, Maria José, Leao, Ana Carolina, Adhikari, Rakesh, Versteeg, Leroy, Tyagi Kundu, Rakhi, Strych, Ulrich, Giordano, Federica, Hotez, Peter J., Bottazzi, Maria Elena, Taraballi, Francesca, Poveda, Cristina, Mancino, Chiara, Pollet, Jeroen, Zinger, Assaf, Jones, Kathryn M., Villar, Maria José, Leao, Ana Carolina, Adhikari, Rakesh, Versteeg, Leroy, Tyagi Kundu, Rakhi, Strych, Ulrich, Giordano, Federica, Hotez, Peter J., Bottazzi, Maria Elena, Taraballi, Francesca, and Poveda, Cristina

Published
2024

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Author

Nelson, Anna, Nelson, Anna, Mancino, Chiara, Gao, Xueqin, Choe, Joshua, Chubb, Laura, Williams, Katherine, Czachor, Molly, Marcucio, Ralph, Taraballi, Francesca, Cooke, John, Huard, Johnny, Bahney, Chelsea, Ehrhart, Nicole, Nelson, Anna, Nelson, Anna, Mancino, Chiara, Gao, Xueqin, Choe, Joshua, Chubb, Laura, Williams, Katherine, Czachor, Molly, Marcucio, Ralph, Taraballi, Francesca, Cooke, John, Huard, Johnny, Bahney, Chelsea, and Ehrhart, Nicole

Published
2024

16. Intramuscular but not nebulized administration of a mRNA vaccine against Rhodococcus equi stimulated humoral immune responses in neonatal foals

Author

Legere, Rebecca M., primary, Poveda, Cristina, additional, Ott, Jeannine A., additional, Bray, Jocelyne M., additional, Villafone, Emma G., additional, Silveira, Bibiana Petri da, additional, Kahn, Susanne K., additional, Martin, Cameron L., additional, Mancino, Chiara, additional, Taraballi, Francesca, additional, Criscitiello, Michael F., additional, Berghman, Luc, additional, Bordin, Angela I., additional, Pollet, Jeroen, additional, and Cohen, Noah D., additional

Published
2023
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21. Mice deficient for G-protein coupled receptor 75 display altered presynaptic structural protein expression and disrupted fear conditioning recall

Author

Speidell, A, Walton, S, Campbell, L, Tomassoni-Ardori, F, Tessarollo, L, Corbo, C, Taraballi, F, Mocchetti, I, Speidell, Andrew, Walton, Sofia, Campbell, Lee A, Tomassoni-Ardori, Francesco, Tessarollo, Lino, Corbo, Claudia, Taraballi, Francesca, Mocchetti, Italo, Speidell, A, Walton, S, Campbell, L, Tomassoni-Ardori, F, Tessarollo, L, Corbo, C, Taraballi, F, Mocchetti, I, Speidell, Andrew, Walton, Sofia, Campbell, Lee A, Tomassoni-Ardori, Francesco, Tessarollo, Lino, Corbo, Claudia, Taraballi, Francesca, and Mocchetti, Italo

Abstract

There are a number of G-protein-coupled receptors (GPCRs) that are considered “orphan receptors” because the information on their known ligands is incomplete. Yet, these receptors are important targets to characterize, as the discovery of their ligands may lead to potential new therapies. GPR75 was recently deorphanized because at least two ligands appear to bind to it, the chemokine CCL5 and the eicosanoid 20-Hydroxyeicosatetraenoic acid. Recent reports suggest that GPR75 may play a role in regulating insulin secretion and obesity. However, little is known about the function of this receptor in the brain. To study the function of GPR75, we have generated a knockout (KO) mouse model of this receptor and we evaluated the role that this receptor plays in the adult hippocampus by an array of histological, proteomic, and behavioral endpoints. Using RNAscope® technology, we identified GPR75 puncta in several Rbfox3-/NeuN-positive cells in the hippocampus, suggesting that this receptor has a neuronal expression. Proteomic analysis of the hippocampus in 3-month-old GPR75 KO animals revealed that several markers of synapses, including synapsin I and II are downregulated compared with wild type (WT). To examine the functional consequence of this down-regulation, WT and GPR75 KO mice were tested on a hippocampal-dependent behavioral task. Both contextual memory and anxiety-like behaviors were significantly altered in GPR75 KO, suggesting that GPR75 plays a role in hippocampal activity.

Published
2023

24. Immunosuppressive potential evaluation of synovial fluid mesenchymal stem cells grown on 3D scaffolds as an alternative source of MSCs for osteoarthritis cartilage studies

Author

Paradiso, Francesca, Lenna, Stefania, Isbell, Reagan, Garcia Garza, Maria Fernanda, Williams, Michael, Varner, Catherine, Mcculloch, Patrick, and Taraballi, Francesca

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease, leading cause of disability in older adults and leads to pain, reduced mobility, and decreased quality of life. Mesenchymal stem cells (MSC) - based therapies are the precursor to all tissues within a joint and their potential in regeneration is complemented by a modulation of the local inflammatory response. The use of MSCS-based therapy for regenerative medicine, specifically OA, is challenged by the need to investigate the ideal MSC source, establish processing of harvesting and culture. Although bone marrow-derived mesenchymal stem cells (BM-MSCs) represent the gold standard in cell therapies for OA, synovial fluid-derived stem cells (SF-MSCs) can be a less invasive, promising alternative. Procedures to extract SFMSCs can be performed during arthrocentesis, arthroscopy or knee surgery with a minimally invasive act allowing personalized autologous therapies. SF-MSCs, isolated from human synovial fluid of patients suffering from advanced OA, retained stemness markers and inflammatory potential in 2D culture condition showing similar morphology and clonogenicity potential compared to BM-MSCs. To further boost their immunomodulatory properties, we coupled SF-MSCs with a biomimetic scaffold made of collagen and chondroitin sulfate (CL CS), previously reported as immune-tuning materials. The 3D culture further promoted immunosuppressive markers expression in SF-MSCs compared to 2D culture. Although ongoing clinical trials mainly used scaffold-free injection of MSCs, combination of mesenchymal cells and biomatrices could provide a useful tool to improve biological outcomes. A combination of SF-MSCs and 3D CL CS biomimetic scaffolds could represent a strong therapeutic effect as cell-based treatment for OA.

Published
2022
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27. Optimization of Biomimetic, Leukocyte-Mimicking Nanovesicles for Drug Delivery Against Colorectal Cancer Using a Design of Experiment Approach

Author

Rampado, Riccardo, primary, Biccari, Andrea, additional, D’Angelo, Edoardo, additional, Collino, Federica, additional, Cricrì, Giulia, additional, Caliceti, Paolo, additional, Giordano, Federica, additional, Taraballi, Francesca, additional, Pucciarelli, Salvatore, additional, and Agostini, Marco, additional

Published
2022
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29. sj-docx-1-tej-10.1177_20417314221138945 – Supplemental material for Osteogenesis in the presence of chemotherapy: A biomimetic approach

Author

Brozovich, Ava A, Lenna, Stefania, Paradiso, Francesca, Serpelloni, Stefano, McCulloch, Patrick, Weiner, Bradley, Yustein, Jason T, and Taraballi, Francesca

Subjects
110599 Dentistry not elsewhere classified, FOS: Clinical medicine, FOS: Biological sciences, 69999 Biological Sciences not elsewhere classified
Abstract

Supplemental material, sj-docx-1-tej-10.1177_20417314221138945 for Osteogenesis in the presence of chemotherapy: A biomimetic approach by Ava A Brozovich, Stefania Lenna, Francesca Paradiso, Stefano Serpelloni, Patrick McCulloch, Bradley Weiner, Jason T Yustein and Francesca Taraballi in Journal of Tissue Engineering

Published
2022
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35. LDL-Based Lipid Nanoparticle Derived for Blood Plasma Accumulates Preferentially in Atherosclerotic Plaque

Author

Boada, Christian A., primary, Zinger, Assaf, additional, Rohen, Scott, additional, Martinez, Jonathan O., additional, Evangelopoulos, Michael, additional, Molinaro, Roberto, additional, Lu, Madeleine, additional, Villarreal-Leal, Ramiro Alejandro, additional, Giordano, Federica, additional, Sushnitha, Manuela, additional, De Rosa, Enrica, additional, Simonsen, Jens B., additional, Shevkoplyas, Sergey, additional, Taraballi, Francesca, additional, and Tasciotti, Ennio, additional

Published
2021
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36. Humanized Biomimetic Nanovesicles for Neuron Targeting (Adv. Sci. 19/2021)

Author

Zinger, Assaf, primary, Cvetkovic, Caroline, additional, Sushnitha, Manuela, additional, Naoi, Tomoyuki, additional, Baudo, Gherardo, additional, Anderson, Morgan, additional, Shetty, Arya, additional, Basu, Nupur, additional, Covello, Jennifer, additional, Tasciotti, Ennio, additional, Amit, Moran, additional, Xie, Tongxin, additional, Taraballi, Francesca, additional, and Krencik, Robert, additional

Published
2021
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39. Improved Posterolateral Lumbar Spinal Fusion Using a Biomimetic, Nanocomposite Scaffold Augmented by Autologous Platelet-Rich Plasma

Author

Van Eps, Jeffrey L., primary, Fernandez-Moure, Joseph S., additional, Cabrera, Fernando J., additional, Taraballi, Francesca, additional, Paradiso, Francesca, additional, Minardi, Silvia, additional, Wang, Xin, additional, Aghdasi, Bayan, additional, Tasciotti, Ennio, additional, and Weiner, Bradley K., additional

Published
2021
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41. LDL-Based Lipid Nanoparticle Derived for Blood Plasma Accumulates Preferentially in Atherosclerotic Plaque

Author

Boada, Christian A., Zinger, Assaf, Rohen, Scott, Martinez, Jonathan O., Evangelopoulos, Michael, Molinaro, Roberto, Lu, Madeleine, Villarreal-Leal, Ramiro Alejandro, Giordano, Federica, Sushnitha, Manuela, De Rosa, Enrica, Simonsen, Jens B., Shevkoplyas, Sergey, Taraballi, Francesca, Tasciotti, Ennio, Boada, Christian A., Zinger, Assaf, Rohen, Scott, Martinez, Jonathan O., Evangelopoulos, Michael, Molinaro, Roberto, Lu, Madeleine, Villarreal-Leal, Ramiro Alejandro, Giordano, Federica, Sushnitha, Manuela, De Rosa, Enrica, Simonsen, Jens B., Shevkoplyas, Sergey, Taraballi, Francesca, and Tasciotti, Ennio

Abstract

Apolipoprotein-based drug delivery is a promising approach to develop safe nanoparticles capable of targeted drug delivery for various diseases. In this work, we have synthesized a lipid-based nanoparticle (NPs) that we have called “Aposomes” presenting native apolipoprotein B-100 (apoB-100), the primary protein present in Low-Density Lipoproteins (LDL) on its surface. The aposomes were synthesized from LDL isolated from blood plasma using a microfluidic approach. The synthesized aposomes had a diameter of 91 ± 4 nm and a neutral surface charge of 0.7 mV ± mV. Protein analysis using western blot and flow cytometry confirmed the presence of apoB-100 on the nanoparticle’s surface. Furthermore, Aposomes retained liposomes’ drug loading capabilities, demonstrating a prolonged release curve with ∼80% cargo release at 4 hours. Considering the natural tropism of LDL towards the atherosclerotic plaques, we evaluated the biological properties of aposomes in a mouse model of advanced atherosclerosis. We observed a ∼20-fold increase in targeting of plaques when comparing aposomes to control liposomes. Additionally, aposomes presented a favorable biocompatibility profile that showed no deviation from typical values in liver toxicity markers (i.e., LDH, ALT, AST, Cholesterol). The results of this study demonstrate the possibilities of using apolipoprotein-based approaches to create nanoparticles with active targeting capabilities and could be the basis for future cardiovascular therapies.

Published
2021

43. The Limitless Future of RNA Therapeutics

Author

Damase, Tulsi Ram, primary, Sukhovershin, Roman, additional, Boada, Christian, additional, Taraballi, Francesca, additional, Pettigrew, Roderic I., additional, and Cooke, John P., additional

Published
2021
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44. MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells

Author

Mazziotta, Chiara, primary, Lanzillotti, Carmen, additional, Iaquinta, Maria Rosa, additional, Taraballi, Francesca, additional, Torreggiani, Elena, additional, Rotondo, John Charles, additional, Otòn-Gonzalez, Lucia, additional, Mazzoni, Elisa, additional, Frontini, Francesca, additional, Bononi, Ilaria, additional, De Mattei, Monica, additional, Tognon, Mauro, additional, and Martini, Fernanda, additional

Published
2021
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50. Biomimetic Nanoparticles Potentiate the Anti-Inflammatory Properties of Dexamethasone and Reduce the Cytokine Storm Syndrome: An Additional Weapon against COVID-19?

Author

Molinaro, R, Pasto, A, Taraballi, F, Giordano, F, Azzi, J, Tasciotti, E, Corbo, C, Molinaro, Roberto, Pasto, Anna, Taraballi, Francesca, Giordano, Federica, Azzi, Jamil A., Tasciotti, Ennio, Corbo, Claudia, Molinaro, R, Pasto, A, Taraballi, F, Giordano, F, Azzi, J, Tasciotti, E, Corbo, C, Molinaro, Roberto, Pasto, Anna, Taraballi, Francesca, Giordano, Federica, Azzi, Jamil A., Tasciotti, Ennio, and Corbo, Claudia

Abstract

Recent studies on coronavirus infectious disease 2019 (COVID-19) pathophysiology indicated the cytokine release syndrome induced by the virus as the main cause of mortality. Patients with severe COVID-19 infection present a systemic hyper inflammation that can lead to lung and multi-organ injuries. Among the most recent treatments, corticosteroids have been identified to be effective in mitigating these catastrophic effects. Our group has recently developed leukocyte-derived nanovesicles, termed leukosomes, able to target in vivo the inflamed vasculature associated with pathological conditions including cancer, cardiovascular diseases, and sepsis. Herein, to gain insights on the anti-inflammatory properties of leukosomes, we investigated their ability to reduce uncontrolled inflammation in a lethal model of lipopolysaccharide (LPS)-induced endotoxemia, recapitulating the cytokine storm syndrome observed in COVID-19 infection after encapsulating dexamethasone. Treated animals showed a significant survival advantage and an improved immune response resolution, as demonstrated by a cytokine array analysis of pro- and anti-inflammatory cytokines, chemokines, and other immune-relevant markers. Our results showed that leukosomes enhance the therapeutic activity of dexamethasone and better control the inflammatory response compared to the free drug. Such an approach could be useful for the development of personalized therapies in the treatment of hyperinflammation related to infectious diseases, including the ones caused by COVID-19.

Published
2020

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