At the San Raffaele-Telethon Institute in Milan, an innovative liver-directed gene transfer platform applicable to various metabolic diseases has been developed thanks to the efforts of the research group led by Alessio Cantore, together with the biotech company Genespire.
Developing gene therapies for severe genetic diseases of childhood has been the goal of Genespire, a biotechnology company set up in 2020 thanks to the Sofinnova-Telethon fund, which has recently received substantial new funding from additional major investors.
In particular, the focus is on the liver, an organ that performs various vital functions, and on the possibility of correcting numerous hereditary defects of metabolism by means of vectors of viral origin capable of transferring the necessary genetic information.
The technology used is the 'workhorse' of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), the one based on lentiviral vectors, i.e. derived from the HIV virus, optimized to transfer therapeutic genes into liver cells.
These vectors have a special feature: when they 'infect' their target cell, they insert their own genetic heritage into its DNA. "This means that the correction we introduce is permanent and persists even if that cell should divide to proliferate, as in the case of a growing tissue or one that needs to be repaired," explains Alessio Cantore, who, together with the institute's director Luigi Naldini is one of the founders of Genespire with Fondazione Telethon and Ospedale San Raffaele.
"A gene therapy of this kind would therefore provide a long-lasting and stable correction: it would therefore be suitable to be administered at a young age and would offer long-term benefits, which is crucial for genetic diseases that already manifest themselves during the first years of life."
This is particularly the case with acidaemia methylmalonic (MAA), a serious genetic disorder that impairs the metabolism of certain amino acids and fats, causing an accumulation of toxic substances. It can manifest itself already after birth and cause metabolic crises, organ damage and severe developmental delays.
Thanks to newborn screening, in Italy, this disease can be diagnosed as early as the first days of life. To date, there is no decisive cure and the only strategy to contain the damage is a low-protein diet combined with the intake of compounds capable of eliminating any toxic residues from the metabolism or increasing deficient metabolic activity. Gene therapy, on the other hand, could change the natural history with a single administration.
'In recent years, we have done a lot of work in our laboratory to optimize the correction of the liver cell genome with lentiviral vectors administered in vivo, i.e., directly into the patient's body,' explains Alessio Cantore. This is a different strategy from the one employed by our colleagues at SR-TIGET to correct blood stem cells in the context of genetic diseases such as metachromatic leukodystrophy or primary immunodeficiencies: in that case, we speak of an ex vivo strategy because the correction with the vector takes place in the laboratory, outside the patient's body. In order to correct the liver cells, we had to construct the viral vector in such a way as to make it 'acceptable' to our immune system so that once infused into the blood, it would not be eliminated. Studies in animal models have shown encouraging results: the vector not only manages to reach the liver but also to give its cells a stable correction, with a beneficial effect even on distant organs, such as the kidneys or the brain, under certain conditions.
The first disease that served as an experimental model for this therapeutic platform was haemophilia, due to the genetically-based deficiency of some of the factors responsible for blood clotting. Thanks to the support of Fondazione Telethon and important industrial partners who believed in the project, Naldini and Cantore demonstrated the potential of this 'in vivo' strategy in both forms of haemophilia, A and B. However, it will be on methylmalonic acidemia that Genespire intends to test this new therapeutic platform for the first time in humans, thanks also to the important funding recently obtained from its investors.
«'Until now, in vivo gene therapy based on HIV-derived vectors has never been tested on patients,' Cantore continues. For haemophilia, drugs are already approved for both forms, including gene therapies based on adeno-associated vectors (AAV). For this very reason, it was decided to prioritize a disease that is not only serious and early-onset, but also more complex and lacking in therapeutic alternatives. Haemophilia will nevertheless remain 'on the radar' of the SR-TIGET researchers, as it represents a very useful model for optimizing liver-directed gene therapy approaches. On the other hand, it will be important to observe the effects of already available gene therapies over time and to assess whether more effective alternatives should be developed".
Another innovative aspect of the gene therapy platform proposed by Genespire is the fact that it is 'off-the-shelf', i.e., standardized and ready-to-use, which means that it does not have to be 'designed' for the individual patient. This approach, which is very innovative in the context of rare genetic diseases, makes it possible to significantly reduce costs and administration time, thus offering wider access to treatments.
Off-the-shelf' therapies thus represent a solution to break down the economic barriers that often limit access to advanced and expensive therapies, paving the way for a future where innovative treatments will not be a privilege reserved for a few, but a real possibility for all those who need them.
