RNA - Genetherapys
Spoke 5 - Inflammatory and Infectious Diseases

The profound impact of RNA-based technologies has transformed the landscape of treating and preventing infectious and inflammatory diseases. A prime illustration is the dominance of mRNA-based vaccines during the SARS-CoV-2 pandemic. Demonstrating rapid development and high effectiveness in eliciting antigen-specific immune responses, these mRNA-based vaccines are now pivotal in suppressing, rather than priming such responses for treating immune disorders like autoimmune diseases, a primary focus of Spoke 5 activities.
Furthermore, Spoke 5 focuses on the exploration of non-coding RNAs as sensitive non-invasive biomarkers. These biomarkers hold the potential for diagnosing, predicting, and stratifying patients with inflammatory, autoimmune, and infectious diseases while presenting novel therapeutic targets. Circulating extracellular vesicles have also gained attention as potential vectors for RNA and molecule delivery, Spoke 5 will dedicate several activities to their characterization and use as both potential vectors and biomarkers.
Overall, Spoke 5 stands at the forefront of research, encompassing both coding and non-coding RNA as therapeutic targets, vehicles, or biomarkers for infectious and inflammatory diseases.
Additional emerging strategies, such as viral vector and non-viral RNA/DNA delivery for cell-specific gene silencing, are gaining prominence as precision drug delivery approaches in inflammatory and infectious diseases. These strategies exhibit improved efficacy and safety profiles, representing innovative ways to target selective cellular and molecular pathways in the treatment of inflammatory and infectious diseases. While gene regulation through viral vectors, as seen in COVID-19 vaccines, is already in use, Spoke 5 extends its focus to immunological considerations. The widespread application of vectors based on viruses capable of infecting human cells may face challenges from pre-existing antiviral immune responses. This includes the presence of neutralizing antibodies that can block the vector, thereby reducing transduction efficiency and the expression of the conveyed gene product. Finally, Spoke 5 is dedicated to exploring and analyzing immunological responses to both viral and non-viral RNA vectors comprehensively.

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Program Who we are Spoke flagships Cross-spoke activities

PROGRAM

Spoke 5 is organized into four primary Work Packages (WPs), each dedicated to advancing cutting-edge research in the fields of vaccines, therapeutic RNA discovery, innovative infection-fighting strategies, and RNA-based drug design and delivery.
WP 5.1 focuses on developing a versatile platform for viral vaccines, specifically leveraging a “replication-deficient” Sendai virus vector to produce an alternative SARS-CoV-2 vaccine. State-of-the-art technologies will assess the immunogenicity and efficacy of vaccines. Additionally, platforms for generating prophylactic drugs will include mRNA-encoding neutralizing antibodies that are under development. Another facet involves engineering innate immune molecules for therapeutic purposes while addressing viral infections and autoimmune disorders.
WP 5.2 focuses on non-conventional strategies to combat challenging bacterial infections and novel viruses. Specific activities include identifying bacteriophages capable of targeting resistant bacteria, employing Genomics-Informed Drug Design (Gen-ID2) technology, and designing aptamers to target and destroy infected cells. The Gen-ID2 technology aligns with efforts in Spoke 2, offering the potential for personalized cancer treatments with reduced side effects.

WP 5.3 is dedicated to discovering circulating RNAs as biomarkers and therapeutic targets in immune and inflammatory diseases. The focus of WP 5.3 extends to analyzing extracellular vesicle-associated non-coding RNAs as potential biomarkers and targets. Establishing a core facility for high-throughput sequencing analysis, initially focusing on Type 1 Diabetes and pulmonary fibrosis, with potential applications in various diseases across different Spokes.
WP 5.4 centers on designing RNA-based drugs and delivery methodologies. The efforts include reprogramming dendritic cells using RNA to address immune pathologies related to transplantation and autoimmunity and developing a platform for cell-based therapy to control graft-versus-host disease and autoimmune disorders. Additionally, WP 5.4 will explore programmable viral and non-viral lipid-based RNA/DNA delivery systems to enhance therapeutic development and delivery.
These comprehensive research initiatives underscore Spoke 5’s commitment to advancing scientific knowledge, fostering collaboration, and contributing to the development of innovative solutions for infectious and inflammatory diseases.

Spoke 5

WHO WE ARE

Università di Siena
Humanitas University
Università degli Studi di Firenze
Università degli Studi di Milano
Università degli Studi di Napoli Federico II Corso Umberto I, 40 80138 Napoli Centralino +39 0812531111 contactcenter@unina.it C.F. 00876220633 PEC ateneo@pec.unina.it
Università degli Studi di Padova
Università degli Studi di Roma “Tor Vergata”
Università di Verona

SPOKE FLAGSHIPS

Several activities within Spoke 5 receive robust support from small and medium enterprises (SMEs) and pharmaceutical companies.
For Work Package 5.2 (WP 5.2), we capitalize on the innovative Genomics-Informed Drug Design (Gen-ID2) platform (Task 5.2.2), designed to selectively recognize and degrade viral genomic RNA. This platform holds immense potential, offering treatments for diseases influencing the genetic profile of affected tissues, aligning with the objectives of Spoke 1 and Spoke 2. The considerable market size for such treatments is promising. Our collaboration with the American start-up, Entropy Therapeutics, further strengthens this initiative. Entropy Therapeutics, having patented carriers for use in the Genomics-Informed Drug Design (Gen-ID2) platform, has committed to granting the National Center favorable patenting rights and supporting the technology’s application development.
The innovative platform for in vitro transfection of monocytes/dendritic cells with mRNA, aiming to generate tolerogenic cells, has been patented. Its development and translation to the clinical setting are being propelled with the support of BioNTech (Germany).
Spoke 5 has established a core facility dedicated to high-throughput sequencing analysis of circulating RNAs associated with multiple blood plasma components. This facility is pivotal in discovering novel biomarkers for therapy response, enhancing precision medicine approaches, and unveiling innovative therapeutic targets.
This strategic initiative amplifies Spoke 5’s commitment to advancing research and fostering collaborations in the pursuit of breakthrough discoveries.

CROSS-SPOKE ACTIVITIES

Ongoing collaborations and synergized efforts are actively driving our research initiatives. In partnership with Spoke 8, we are undertaking an in-depth analysis and development of extracellular vesicles as potential therapeutic vectors. This involves the targeted delivery of RNA molecules into specific cells of interest, such as insulin-producing beta cells and lung cells. Given the utilization of high-throughput RNA-omics technologies and the anticipated substantial volume of data from various sample sources, Spoke 5 will be closely engaging with the biocomputing infrastructures established in Spoke 7. This collaboration aims to streamline -omics data analysis and facilitate data access for the entire National Center.