Spoke 1 - RNA Genetherapy

Gene therapy may represent the only definitive treatment for most monogenetic diseases, which currently affect between 6 and 8% of the world’s population. The overall objective of Spoke 1 is to develop cutting-edge gene (GT) and RNA therapies (RT) for paradigmatic and incurable genetic diseases. Such an endeavor includes collaborations with pharmaceutical and biotech companies for the licensing, development, and marketing of these therapeutic innovations.

Spoke 1 is organized across six Work Packages (WPs) that focus on skin, eye, blood, storage diseases, kidney, and neuromuscular and neurometabolic disorders. WPs make use of a new generation of viral vectors, stem cell-mediated, systemically or locally delivered siRNA, miRNA, shRNA, ASO, antagoMIRs, SINEUPs and RNAs, nanomedicine-based approaches, and gene editing (GE) technologies.

Spoke 1 activities seek to define early lead candidates, provide preclinical proof of concept, and implement phase I and phase II clinical trials. Testing facilities’ support provides preclinical drug development and Good Manufacturing Practice (GMP) certifications for cell and gene therapy products. Spoke 1 activities include Good Laboratory Practice (GLP) testing for toxicity, target validation, and optimization of in vitro and in vivo models.

PROGRAM

Spoke 1 aims to foster innovation that accelerates translational research from “bench to bedside” by developing gene therapies and RNA therapeutics to treat a select group of incurable genetic diseases. Spoke 1 focuses on specific organ systems and disease-oriented Work Packages (WPs). Key activities are framed behind defining early lead candidates (Technology Readiness Level, TRL, 1-2), demonstrating preclinical proof of concept (TRL 3-5), and implementing phase I and phase II of clinical trials (TLR 6-9).

Specific research programs define each of Spoke 1 WPs.

WP 1.1 SKIN – Epithelial stem cell-based gene therapy (GT) for genetic skin diseases such as Epidermolysis bullosa and Lamellar ichthyosis.
WP 1.2 BLOOD – GT and RNA therapy (RT) for blood-related genetic diseases, including Sickle Cell disease, thalassemia, hemochromatosis, Ferroportin Disease, Hemophilia A, and rare red blood cell diseases.
WP 1.3 EYE – Corneal stem cell applications, gene editing (GE), and microRNA therapy for genetic eye diseases like Meesmann corneal dystrophy, inherited retinal degeneration, and optic neuropathies.
WP 1.4 STORAGE DISEASES – Hematopoietic stem cell-based GT and RT for genetic storage diseases such as Lipofuscinosis 1, neuropathic storage diseases, mucopolysaccharidosis type VI, and Pompe Disease.
WP 1.5 KIDNEY – RT and GE therapy for genetic kidney diseases including Birt-Hogg-Dubé (BHD) syndrome, Tuberous sclerosis complex (TSC), and Alport syndrome.
WP 1.6 NEUROMUSCULAR AND NEUROMETABOLIC DISORDERS – RT, GE, and GT targeting mitochondrial, neurometabolic, neurodevelopmental, and neuromuscular diseases, such as Friedreich’s ataxia, mitochondrial diseases of nuclear origin, Duchenne muscular dystrophy, Rett syndrome, PRUNE_1disease, and Central core disease.

SPOKE FLAGSHIPS

The Spoke 1 Flagship is a state-of-the-art research laboratory at the Center of Genomic Medicine and Rare Diseases of UNIMORE dedicated to the study of genetic diseases using modern 3D culture technologies and organoids, as well as the latest Next-Generation Sequencing technologies. Organoids, particularly those based on isolated pluripotent or adult stem cells that self-assemble into complex 3D structures, have emerged as an innovative model very similar to human organs. This allows the study of biological processes in a physiological context without the use of animals. Traditional 2D cell cultures and animal models often fail to replicate the complexities of human diseases. Advanced 3D culture systems and organoids overcome these limitations, offering a more accurate and ethical alternative for studying human liver diseases and testing potential treatments.

Among the activities planned at the National Center is the bio-functional assembly of 3D organoids from patient-derived tissues and/or genetically engineered human progenitor stem cells and the use of 3D bioprinting, a manufacturing process that uses natural or synthetic biomaterials, combined with living cells, to develop structures that mimic the behavior and architecture of natural tissues. This will provide a unique platform for studying genetic diseases and testing new drugs in a laboratory equipped with the latest technologies for cell culture, imaging systems, molecular biology tools, 3D-bioprinting and high-throughput screening facilities to promote advanced research, particularly in genetic liver diseases. These resources will facilitate innovation in genetic disease research, contributing to the development of more effective and personalized treatments for patients with genetic liver diseases and other organ-related conditions.

CROSS-SPOKE ACTIVITIES

Active collaborations and coordinated efforts are underway with both horizontal and vertical spokes. Spoke 3 will focus on neurodegenerative, neurodevelopmental, and neuromuscular disorders. Spoke 6 will aim at the development of RNA tools and strategies.
Spoke 7 focuses on the implementation and optimization of biocomputing strategies. Spoke 8 seeks to exploit delivering/targeting approaches, while Spoke 10 is devoted to the sharing of protocols and medicinal products.
Spoke 1 affiliates also include the Chiesi Group, a prominent Italian pharmaceutical company with a mission to identify new and advanced therapies for rare diseases. The Chiesi Group actively engages as a partner by significantly contributing to specific projects within Spoke 1.

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PROGRAM

WHO WE ARE

SPOKE FLAGSHIPS

CROSS-SPOKE ACTIVITIES