RNA - Genetherapys
Spoke 9 - Competence Center on RNA Drug Pharmacology

Given the emerging nature of the field of nucleic acid (NA) therapeutics, our understanding of the methodologies required for studying their pharmacokinetics (PK), pharmacodynamics (PD), and toxicology remains limited. Consequently, research should focus on developing the necessary tools to evaluate the biodistribution, metabolism, and activity of NA-based drugs at both desired targets and unintended sites of action. Additionally, considering their known immunogenicity and potential for off-target effects, new pathways should be explored for appropriate immune-toxicological evaluations.
Spoke 9 orchestrates a wide array of competencies and facilities to advance science-based methods for analyzing PK, PD, and toxicology. These advancements are crucial for the clinical translation of RNA drugs in light of the current regulatory framework on medicinal products. The current process is tailored according to a case-by-case basis, which is complicated by the biological instability of RNA, its limited ability to cross biological barriers, and the availability of different categories of RNA-based therapies.
Standard analytical methods suitable for small molecules, such as Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), along with methods specifically applied to RNA drugs (northern blot, real-time PCR, ELISA, fluorescent probes), offer limited information for determining absorption, distribution, metabolism, excretion, and toxicity (ADMET profiles), and their connection with Pharmacodynamics Parameters. Moreover, there is plenty of room for implementing tiered approaches for characterizing RNA and the loading of nanosystems to ensure that the next generation of medicinal products falls within regulatory standards.
The ultimate goal is to leverage the interdisciplinary and trans-sectoral expertise of Spoke 9 to establish an RNA-drug Competence Center capable of creating novel protocols tailored to RNA drugs. This will accelerate product development by ensuring qualitative parameters that are suitable for the proposal and acceptance of regulatory agencies. Consequently, companies and research centers involved in RNA-drug development can take advantage of the implementation and standardization of these novel protocols.
The ambition of Spoke 9 is to build upon its long-term expertise in Biotechnology and Pharmacology to organize the Competence Center. The center is where top academics from some of Italy’s most prestigious universities and research centers such as the University Federico II of Naples, Rome, Padua, Pavia, Humanitas, and National Research Council of Italy – CNR collaborate synergistically with national and international pharmaceutical, diagnostic companies, and contract research organizations (CRO). The goal is to become a reference point dedicated to advancing RNA therapeutics.

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Program Who we are Spoke flagships Cross-spoke activities

On 20-21 June 2024 Spoke 9 organised the congress “The Pharmacology of RNA Drugs: An Unmet Pharmacological Need Tackled by the National Centre of RNA Drugs” hosted by the University of Milan. The Abstract Book including all abstracts is available here.

SP9 Abstract Book

PROGRAM

Spoke 9 operates along short and long-term goals.
Short-term goals include leveraging its current expertise in regulatory sciences, by aligning them with the European Medicines Agency (EMA) and the American Food and Drug Administration (FDA) according to guidelines on bioanalytical method validation. We will develop and optimize standard analytical techniques, specifically Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), for quantifying and understanding the biodistribution of RNA therapeutics. Such goals will be applied in clinical and preclinical distribution studies.
Additionally, we will utilize research from vertical Spokes to identify biomarkers suitable for verifying the activity of the RNA drug.

Long-term goals include testing and optimizing innovative concepts to expedite preclinical studies. This involves combining current steps required for ADMET profile studies with new protocols tailored for RNA drug development, based on a novel rational flow. The Competence Center for RNA drug pharmacology will integrate these novel concepts into the research program, creating new protocols accepted by regulatory agencies, where innovative biomarkers, combined with reporter systems, are suitable for in vivo imaging. These protocols aim to consolidate pharmacokinetics and pharmacodynamics studies into a single step, significantly improving sensitivity, reproducibility, and accuracy of results. Simultaneously, there will be a substantial reduction in the number of animals euthanized, aligning with the Replacement, Reduction, and Refinement principles (3Rs).

Spoke 9

WHO WE ARE

Università degli Studi di Milano
ANTARES VISION GROUP
Chiesi Farmaceutici
Consiglio Nazionale delle Ricerche
Dompé
Humanitas University
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 Pavia
SAPIENZA Università di Roma

SPOKE FLAGSHIPS

Enabling technologies for RNA drug discovery & development

  • Adapting existing technologies under the current regulatory framework.
  • Creating novel technologies to expedite RNA drug development.
  • Validating protocols for regulatory compliance.

CROSS-SPOKE ACTIVITIES

Spoke 9 works in close collaboration with the vertical Spokes 1, 2, 3, 4, and 5. These collaborations will guide the design of Pharmacokinetic (PK), Pharmacodynamic (PD), and Toxicokinetic (Tox) studies for the preclinical dossier while actively participating in the development of RNA drugs for the most promising agents identified by the National Center. The collaboration with the horizontal Spoke 6 will assess the PK, PD, and Tox impact of chemical modifications to drugs and will offer the delivery tools developed by Spoke 8. As an integral component of the project, Spoke 7 follows and ensures each step in the data management and analysis, including the application of Artificial Intelligence (AI) for unsupervised methodologies in detecting reporter activity through imaging.

The support of affiliated companies with Spoke 9 is crucial for creating scalable protocols for industrial use. Their support will allow for the development of efficient imaging tools, conducting quality assessments, initiating studies at locations that follow Principles of Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), and facilitating the translation of research products into standard and applicable technologies for RNA drug development.

Public-private partnerships are key to the success of Spoke 9, as collaboration with affiliated companies is indispensable for achieving the objectives of all Work Packages. Notably, the collaboration with Dompé Pharmaceuticals focuses on RNA vaccine immunotoxicology to develop new methods and in vivo models for immuno-toxicological evaluations, as well as GLP toxicological studies. Collaboration with the Chiesi Group centers on defining technologies for studying RNA drug distribution, with a specific emphasis on translating dosage studies conducted in laboratory animals into doses for human use. Antares Vision contributes to designing quality control methodologies and provides smart data and tools for the digitalization of the process. Throughout the three-year program, Spoke 9 is expected to engage with a majority of the companies currently present in the National Center, particularly for establishing technology transfer operations at the national and international levels.