by Chiara Daina
Little Simone, 3 years old, affected by AADC deficiency, which affects the nervous system. Children already treated in other countries can sit, stand with help, eat on their own, some even walk and talk
For the first time in Italy, at the Umberto I university hospital in Rome, an innovative gene therapy was administered to a three-year-old child for the treatment of a very rare disease that affects the nervous system. The capital’s hospital is the fourth center in Europe to have been authorized for the use of the drug, which contains Eladocagene Exuparvovec and which is injected directly into the brain, and the only one of these to be public. The other specialist structures are private: two are located in France, in Paris and Montpellier, and the third in Germany, in Heidelberg. The pathology against which gene therapy is aimed is called aromatic amino acid decarboxylase (Aadc) deficiency and is caused by the lack of the Aadc enzyme, necessary for the production of dopamine, which, if present at low levels, causes a series of serious symptoms: hypotonia ( decreased muscle tone), hypokinesia (reduced or slow voluntary body movements), oculogyric crises (involuntary rotation of the eyeballs in a fixed position, often sideways or up), mental retardation, nasal congestion, sweating, and temperature spikes sudden drooling (oversalivation). There are about 200 cases worldwide, of which 16 in Italy.
Improve motor and cognitive function
Most patients cannot walk, move their arms, or lift their head. The most severe cases, with difficulty swallowing, live on an intubated bed – declares Francesco Pisani, director of the complex operational unit of child neuropsychiatry of the Umberto I polyclinic, identified as a national reference center for the Aadc deficit, where little Simone (this is the child’s name) received the diagnosis –. So far, drugs have been used for these patients to control the symptoms but they do not help develop neuromotor skills. In 2022, the European Medicines Agency (EMA) gave a favorable opinion on the marketing in the 27 Member States of the European Union of advanced gene therapy based on Eladocagene Exuparvovec, capable of improving motor and cognitive function. But then it is up to the national regulatory agencies to start the process for placing the treatment on the market in their own country. While waiting for the Italian Medicines Agency (Aifa) to conclude the procedure, through a decision dated 9 May 2023, it authorized the dispensing of the medicine by resorting to the national fund for orphan drugs established by law 326 of 2003, which allows access to promising drugs before their marketing for particularly serious pathologies. The value of the therapy (which involves a single infusion) of 3.5 million euros excluding VAT.
The intervention
An extraordinary result – comments Fabrizio d’Alba, director general of the Umberto I hospital -. The administration took place through a stereotaxic intervention under narcosis, that is, thanks to the support of magnetic resonance an intracerebral injection was carried out (in an area of the brain called putamen, ed) also used for the treatment of a series of pediatric and adult neurological disorders. The operation was performed by a team of our excellent neurosurgeons whom I thank personally, as well as the whole team of experts, the managements and operating units involved, anesthesiologists, surgeons, resuscitators, without forgetting the hospital pharmacy, clinical engineering and all the nursing staff. Simone’s splendid smile a few hours after waking up – says D’Alba – and his resignation after a few days were the greatest reward for the extraordinary effort made by all the players in this enterprise. The magnetic resonance room was adapted into a neurosurgery room and here for almost a month the team practiced the procedure by simulating the pre- and post-surgery phases.
Gene replacement
The Aadc deficiency is the first neurological disease that is corrected by replacing the defective gene, which determines the deficiency of the enzyme and therefore the pathology itself. The healthy gene contained within a vector based on adeno-associated virus serotype 2 injected into a group of neurons located in the putamen, one of the parts of the brain explains Pisani. The EMA has authorized the orphan drug (those used for the treatment of rare diseases are called) – he writes in a note – “in exceptional circumstances” because it was not possible to obtain complete information on the drug due to the rarity of the disease”. What does it mean? “While waiting to demonstrate its long-term efficacy and safety on a larger sample of patients, the drug can only be prescribed for the most serious cases aged 18 months or more. Symptoms usually appear in the first six months of life and patients who have been treated globally with gene therapy up to now are up to about 10 years of age. In Italy the only eligible case was that of Simone explains Vincenzo Leuzzi, former director of the child neuropsychiatry of Umberto I, who diagnosed him with the disease. “The first interventions with gene therapy were carried out about ten years ago in Asia, in Taiwan and Japan, and a few months ago they started in Europe. This treatment enabled the treated children to sit up, stand with help, eat on their own, and some even walk and talk.
Successful procedure
In March, Simone’s parents had written a letter to the Prime Minister asking for access to gene therapy, the only hope of a cure for their son. Thanks to the collaboration between the Umberto I polyclinic and Aifa, times have been shortened and regulatory obstacles have been circumvented. The child was hospitalized on 4 May in the child neuropsychiatry ward of Umberto I. The surgery was performed on 22 May and lasted more than 8 hours. After two weeks Simone was able to return home to Sicily. The procedure was successful and there were no side effects. In a month we will begin to see the first results. The child will be monitored at three months, six months and 12 months. Then the checks will be annual. Once the neuropsychomotor process restarts, the permanent conquest concludes Pisani.
June 28, 2023 (change June 28, 2023 | 09:38)
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