A researcher at the Telethon Institute for Gene Therapy (TIGET), in Milano, that specialises in gene therapies for rare diseases. Credit: Eric Vandeville/Gamma-Rapho via Getty Images.
In the summer of 2020, Italy was still in the grip of the first COVID-19 pandemic wave when Reithera, an Italian biotech company, entered the race for a vaccine. A year later, government funding for the project was suspended. More recently Modena-based Holostem, which produced the first stem cell medicine in Europe, found itself in crisis when its biggest private shareholder withdrew support.
Lack of both public funding and of private investments frustrates Italian efforts to bring advanced therapies from the lab to patients. The country invests around €3.3 billion in medical research, most of which goes into the last steps of the drug supply chain, aiming at improving products, drugs’ administrability, and packaging. This approach, together with Italy’s advanced manufacturing capabilities, has made the country a leading pharmaceutical manufacturer in Europe, with €34 billion in production value and 67,000 employees in the sector in 2021. But, the nation’s scientists would like to see more innovative products being discovered and trialed within the country.
The newly funded National Center for gene therapy and drugs based on RNA technologies, that clusters 32 research institutes, 16 pharmaceutical companies, and one of Italy’ largest banks may change that. Through a hub at the University of Padova, 10 ‘spokes’ will discover and design new drugs in major disease areas, or provide technology and platforms. The consortium’s €320 million funding mostly comes from the EU’s ‘Next Generation Europe’ programme and will mainly cover personnel costs for the almost 900 permanent scientists and the 400 postdocs and PhD students.
“Our national centre intercepts a historic moment for healthcare systems as they move towards personalized medicine,” says Rosario Rizzuto, former rector of the University of Padova, and president of the foundation. For rare diseases and personalized treatments, there are too few patients to make drugs profitable. “They are not necessarily a priority for big pharma,” adds Rizzuto, “but if we find new technology transfer platforms, we can lower costs”.
Gene therapy is the paradigm of a tailor-made medical approach, as it involves modifying a patient's own stem cells (with DNA, RNA, or a viral vector) and reintroducing them to better fight a disease, usually a rare, inherited one. The new centre has two spokes dedicated to gene therapy, one on genetic diseases, led by the University of Modena, and Reggio Emilia, and one on preclinical development, GMP manufacturing, and clinical trials of gene-modified somatic cells (GTMPs), led by the Paediatric Hospital Bambino Gesù (OPBG) in Rome.
“The national center will allow us to make a leap forward by strengthening our facilities, personnel, and synergy opportunities,” says Luigi Naldini, director of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), part of both spokes. SR-Tiget has marketed two genetic therapies that can cure a rare immunodeficiency and a rare neurologic disease, respectively. Naldini wants to continue engineering hematopoietic stem cells to target metabolic diseases, immunodeficiencies, and thalassemia-like disease. Scientists will also use CRISPR technology to modify the epigenome, the chemical changes that affect the activity of genes.
RNA technologies offer another route to personalized medicine, in particular for cancer. “In the next future, the doctor could search for aberrant proteins from a simple biopsy, and synthesize mRNAs that produce those proteins,” explains Alberto Boffi, coordinator of the cancer spoke for the University of Rome La Sapienza, “reinjection of that aberrant mRNA into the body would stimulate an immune response against the protein itself”. Such processes take place in a hospital and are extremely expensive. The challenge, says Boffi, is to reduce costs and find a way for industry to make them profitable. The spoke follows around 30 projects, 10 of which are patented. Some are in an advanced stage, like a drug based on microRNA developed by the University of Catanzaro that has passed phase 1 clinical trial and a therapy based on RNA aptamers from the University of Turin.
Neurodegenerative diseases are also in the centre’s sights, and the Italian Institute of Technology based in Genova leads a spoke dedicated to them. “RNA allows targeting any genomic part in the brain,” says coordinator, Stefano Gustincich. The 120 scientists of the spoke want to produce two kinds of molecules: non-coding RNAs that could be used as targets or therapeutics; new types of mRNA that, starting from the knowledge acquired from the COVID-19 research, could lead to vaccines for Alzheimer's or Parkinson’s diseases. “We want to file at least one new drug for a clinical trial by the end of the project,” says Gustincich.
As nucleotides (the basic units of DNA and RNA) are extremely fragile and degradable, one of the main challenges is to deliver them precisely to the target organ, bypassing the blood-brain barrier in the case of the brain. The University of Naples coordinates a spoke that develops the platforms for RNA/DNA delivery and will explore vectors such as polymeric and lipid nanoparticles, exosomes to target cancer, and biodegradable polymer microneedles to deliver RNA-based vaccines. “We will bring forward prototypes fabricated with robust and scalable technologies that can deliver nucleic acids to their target in the body,” says Fabiana Quaglia, from the University of Naples.
In Naples, the national centre will also build a €20 million GMP facility for RNA production. “This is the first facility of this kind in Italy that stems from public funding and not from industry,” says spoke coordinator, Angela Zampella. In the 5,000 m2 facility, RNA-based drugs will be formulated, synthesized, and tested up to phase 1 or even early phase 2 clinical trials. “A GMP facility is key in accelerating RNA therapeutics toward the clinic,” says Zampella. It should start operating in 2025, and then continue working as a service facility for pharmaceutical companies and for hosting clinical trials, says Zampella.
In the delivery spoke, drug companies, Dompé, and Chiesi, will help to establish suitable tests to meet key specifications for reproducibility, while Stevanato will deal with new lyophilization methodologies in syringes and cartridges. Other actors include big companies like Sanofi and AstraZeneca, while Banca Intesa “will assist in finding new financial opportunities for start-ups,” Rizzuto says. It remains to be seen how much of this engagement will stay once public funding is gone.
The question of how to continue after 2026 is existential. “Big pharma is now dismissing investments in drugs for rare genetic diseases as the current model is not sustainable,” says Naldini. For gene therapy, he proposes a non-profit kind of model where the production pipeline from drug discovery to GMP-based studies stays within publicly funded institutions. For RNA technology, Boffi proposes a model that is also based on public funding, but where industry and private capitals step in at an earlier stage of the production pipeline. The public nature of these approaches could allow for fewer regulations and preclinical studies, factors that contribute to the extremely high costs of these therapies.
New business models would require adequate public funding to guarantee affordable drugs. “Italy has to decide between being a net payer and consumer of advanced therapies, or being among those who develop them, thereby making these therapies accessible to patients”, says Rizzuto.
