Developing a neonatal drug therapy and an in utero fetal gene therapy for Leigh syndrome. This is the ambitious project coordinated by Dr. Dario BrunettiResearcher at the Department of Clinical and Community Sciences of the State University of Milan and Principal Investigator at theCarlo Besta Neurological Institutewinner of the Multi-round call promoted by Fondazione Telethon which selected 22 research projects from all over Italy dedicated to rare genetic diseases. The project received funding of 240 thousand euros and will last two years. The study will also include Drs. Alessia DiDonfrancesco e Alessia Adelizzitogether with dr. Ivan DiMeo and to Dr. Valeria Tiranti of the Carlo Besta Neurological Institute.
Leigh syndrome is one of the most common mitochondrial diseases in childhood, affecting 1 in 36,000 newborns. It is a neurometabolic disease that affects the central nervous system, particularly the brainstem and cerebellum. Affected children present with progressive delay in psychomotor development and neuromuscular disabilities, leading to death in the first three years of life.
One of the main causes of this disease is the mutation of the SURF1 gene, involved in the correct functioning of mitochondria, the cell’s energy centers.
Recent studies conducted by Dr. Brunetti’s research group and Prof. Alexander Prison of the University of Dusseldorf have allowed us to understand how SURF1 mutations negatively impact neurodevelopment by causing a metabolic block in the cell that hinders the correct differentiation of neurons. Hence the intuition that a targeted and very early therapeutic intervention or a fetal gene therapy approach could represent a promising strategy to counteract the development of this pathology. Thanks to the project funded by Telethon, these two therapeutic approaches will be studied with research conducted on the porcine model of Leigh syndrome. In the case of pharmacological therapy, we will try to test a class of drugs that inhibit phosphodiesterase 5, which have given positive responses in a European trial conducted on in vitro models, with the aim of restoring cellular metabolism during postnatal neurological development.
The fetal gene therapy to be administered in utero, developed by Dr. Brunetti together with Professor Nicholas Persicofetal surgeon at the Policlinico Hospital and professor of Obstetrics and Gynecology at the Department of Clinical and Community Sciences at the State University of Milan, aims to solve the genetic deficit at the root by reinserting the correct version of the defective gene into the fetus before birth via ultrasound-guided injection in the uterus. The choice to intervene during the fetal phase offers many advantages over postnatal gene therapy as it is possible to correct the genetic defect before irreversible pathological processes set in, it takes advantage of a phase of development in which the Blood-Brain Barrier is still permeable, allowing for better delivery of the therapeutic gene into the central nervous system, the immature immune system and the small fetal size allow for a reduction in the dose of virus to be used, limiting costs.
The minimally invasive approach of In Uterus Fetal Gene Therapy has the potential to be easily transferred to pregnant women to treat many genetic diseases. Few groups in the world are working on this innovative technique, which confirms the excellence of the two Milanese hospital centers and the cutting-edge level of the University of Milan.
“The preclinical development of a new therapeutic strategy for a rare disease represents an important step towards the translation of the future therapy to patients. In particular when it is conducted on a Large Animal Model given the greater proximity to humans both in anatomical and metabolic terms. Often, as in our case, we get there after years of research conducted on simpler models and thanks to the contribution of many colleagues who every day with their work have added a new piece of knowledge on the mechanisms of this disease. Winning a Telethon call is always a great emotion given the very high level of competition. It is a victory that I share with all the colleagues involved in this multidisciplinary study that involves biologists, gynecologists and veterinarians” – underlines the researcher Dario Brunetti.
The generation of pregnancies in sows with embryos carrying Leigh Syndrome that will be used for in utero gene therapy is carried out at the authorised Avantea stable in Cremona by Dr. Robert Dukes assisted by Dr. Andrea Perotfrom Dr. Maria Barandalla and by dr. Mark Scaglia.