The Italian Medicines Agency - AIFA has given the green light for the world's first clinical trial of the drug Mirtazapine in Rett Syndrome,  MirtaRett, after receiving approval from the national ethics committee for paediatric studies. 

The trial is coordinated by the University of Trieste and will be conducted in the main Italian referral hospitals for patients suffering from Rett Syndrome. It is entirely supported by non-profit grants, particularly the non-profit project ‘Angelini for future ’ from Angelini Pharma SpA, together with the Canali Onlus, Ico Falck Onlus and Amadei and Setti Onlus Foundations. The trial will be managed by the consortium for biological and pharmacological evaluations (Consorzio per Valutazioni Biologiche e Farmacologiche, CVBF), a non-profit organisation providing services for clinical research in Italy. 

The actual start of the trial will take about two months, during which UniTS, the coordinating centre, and the four clinical centres in Milan, Genoa, Siena and Messina, will set up the organisational machinery for the recruitment and treatment of the patients. The patients are exclusively female, as Rett syndrome is a genetic disorder that affects 1 in 10,000 girls and is the second most common cause of intellectual disability in females worldwide (Petriti et al. Systematic Reviews (2023) https://doi.org/10.1186/s13643-023-02169).

The trial will involve a total of 54 patients aged between 5 and 40 years. They will be divided into three groups of 18 with varying age brackets (5-10, 11-17 and 18-40 years).

Rett syndrome is a genetic disorder caused by unpredictable mutations of the MECP2 gene in the reproductive cells (spermatozoa or oocytes) of completely healthy parents. Symptoms appear in the second year of life when girls begin to speak and walk, displaying rapid regression of speech and the inability to make voluntary hand movements. In later years, girls develop epileptic seizures and respiratory difficulties, which are the main cause of death. Many patients reach adulthood, albeit with severe physical and cognitive disabilities. 

Restoration experiments on the mutated gene conducted in animal subjects have demonstrated that the disorder can be completely reversed, but to date there is still no definitive cure. 

The project started in 2009, thanks to funding from Telethon, Fondazione San Paolo, Fondazione Casali, Beneficentia Stiftung and the parent associations AIRETT Onlus and ProRett Ricerca Onlus. Across15 years of study carried out in the laboratory directed by Prof. Enrico Tongiorgi at the Department of Life Sciences at the University of Trieste, abundant experimental evidence of Mirtazapine's efficacy in the recovery of certain symptoms has been collected. Further evidence in favour of the drug was then gathered through a retrospective investigation in collaboration with the Rett Reference Centre at Le Scotte Hospital in Siena, where the drug was administered as standard treatment for anxiety, repetitive behaviour and sleep disorders for a period of 1 to 5 years in 40 adult Rett patients. In addition to the beneficial effects the drug had on anxiety and sleep, the study also revealed it as being beneficial to slowing the progression of Rett syndrome, demonstrating improvements in some typical symptoms such as self-harm, irritability, motor difficulties and loss of communication skills. 

‘At the moment, no one has been able to test the effects of this drug in girls suffering from Rett syndrome yet,’ said Prof. Tongiorgi, ‘We therefore believe it is necessary to proceed with a rigorous clinical trial like the one proposed in the MirtaRett project. We have set ourselves the goal of keeping this project entirely in Italy, involving the main referral clinical centres. The trial will test the efficacy of the drug on general symptoms and in particular on motor skills, such as the use of the hand, the ability to communicate and on psychological disorders. We will also monitor the quality of sleep and the basic parameters of breathing and the heart, thanks to a new Italian-made smart T-shirt that we have tested, allowing us to make important discoveries on breathing defects in these patients.’ 
The study also involves monitoring the stress levels of caregivers and detecting biomarkers in the blood, such as neurotrophic factors, which are useful for assessing the effects of the drug on developmental recovery and plasticity of the nervous system.

Every clinical trial has high costs, but thanks to the non-profit nature of the project, it has been possible to reduce them considerably and, thanks to the generosity of donors, the hospitals in Messina, Milan and Siena will also be equipped with the instrumentation to conduct the actigraphy, and 54 smart T-shirts will be purchased. 

Centres and researchers involved in the experimentation:

Coordinator - Prof. Enrico TONGIORGI, Department of Life Sciences, University of Trieste.
Partner 1 – Prof. Maria Paola CANEVINI, Dr. Ilaria VIGANÓ, ASST Ospedale Santi Paolo Carlo - Via di Rudinì 8; Milano; Prof. Aglaia VIGNOLI (MD) ‘Statale’ University of Milan.
Partner 2 – Prof. Lino NOBILI, Dr. Giulia PRATO – Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Sciences (DINOGMI), University of Genoa - Child Neuropsychiatry Unit, Research Hospital, Giannina Gaslini Institute, Genoa.
Partner 3 – Dr. Salvatore GROSSO, Dr. Claudio DE FELICE – Rett Syndrome Research and Experimentation Centre - Paediatric/Neuropaediatric Unit, Mother and Child Department – Polyclinic ‘Santa Maria alle Scotte’, Siena.
Partner 4 – Prof. Gabriella DI ROSA, Dr. Antonio NICOTERA - ‘Gaetano Barresi’ Department of Human Pathology of Adults and the Age of Development, ‘G. Martino’University Polyclinic, University of Messina.