Correcting genes before birth: the new frontier

Correcting a genetic mutation before it causes irreversible damage. This is the ambition of in utero gene therapy, an emerging field of foetal medicine that aims to intervene before birth, when organs are still developing and the foetus' immune system is more tolerant. "The idea is to anticipate the treatment of serious diseases with neonatal onset, transforming them into potentially curable conditions," explain Dario Brunetti (Fondazione Irccs Istituto Neurologico Carlo Besta) and Nicola Persico (Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico di Milano), among the protagonists of a preclinical study recently conducted in Italy on a large animal model.

In their work, the researchers developed a minimally invasive technique for the ultrasound-guided intrauterine delivery of viral vectors. Tests were conducted on pig foetuses - a model particularly suited to human-like size, anatomy and foetal development - to assess the feasibility of the procedure and its short-term effects. 'This is the first significant translational experience in Italy on this front,' they point out. The study did not address a specific pathology, but laid the technical and safety foundations for future therapeutic protocols.

The potential applications are numerous, but require early prenatal genetic diagnosis. "We are talking about pathologies in which the damage already starts during pregnancy," they explain. Among these, Brunetti and Persico cite severe mitochondrial diseases, which already impair the development of the brain and other vital organs in utero; neurodegenerative diseases such as Spinal Muscular Atrophy (Sma) type 1, which damages motor neurons from the late stages of pregnancy. "In utero gene therapy could also treat congenital muscular dystrophies, which lead to muscle weakness and fibrosis as early as birth; metabolic diseases such as Wilson's disease, in which the accumulation of toxic metabolites begins before birth; and congenital lung diseases, such as surfactant deficiency syndromes, which cause neonatal respiratory failure, and cystic fibrosis, to reduce lung damage as early as the foetal stage."

However, there are still many limits to be overcome. First and foremost: the safety of the procedure for mother and foetus. Gene therapy in utero carries risks such as infection, premature birth or foetal injury. Moreover, the therapy's effectiveness depends on uniform distribution in the various organs, which is not always guaranteed: 'in our animal models we observed a preferential concentration in the liver, less in the brain,' explain researchers Brunetti and Persico. For each individual genetic disease, it will be necessary to find the best compromise between time of administration and dose. If too low, there is a risk of 'dilution' of the transgene as the organism grows, making its benefit transient. Conversely, high doses could cause liver, heart or kidney toxicity, already observed in some postnatal clinical studies. Currently, the two researchers together with the Avantea team (a Cremona-based biotech company specialising in animal reproductive technologies) are conducting various experiments to assess the technique's efficacy and safety on a pig model of Leigh's Syndrome (a serious paediatric mitochondrial disease). 'After these experiments we will have more robust data that would allow an eventual translation of the technique to patients,' they state.

To date, there are no active clinical trials in Italy, but the country is in line with most of Europe. Further ahead are the United Kingdom and the United States: the British Mhra has already approved clinical trials of fetal cell therapy, and research groups in Philadelphia and Houston are engaged in experimental trials for immunodeficiencies.