Gene injection and “cell juice”: the research feats financed by the Telethon

On December 8 and 9, the traditional television high mass of the French Association against Muscular Dystrophy will take place, with 30 hours of live broadcast and thousands of events throughout France. When the Telethon was born in 1987, the genetic mutation responsible for Duchesne muscular dystrophy had just been discovered, but no treatment existed for these neuromuscular genetic diseases. Since then, despite the numerous criticisms of which it has been the subject, the event has raised around 90 million euros each year, and the therapeutic successes that it has financed have become more numerous. Overview, ten days before the 2023 edition.

Proximal spinal muscular atrophy, or “SMA”, is a degeneration of motor neurons in the spinal cord, which generally affects the innervation of the lower limbs. There are 5 types with very diverse life expectancies, from death in the first weeks after birth to an almost normal life. SMA affects around 124 new people per year in France (incidence of 1/6000). The severity of the disease requires multidisciplinary care with nutritionist, respiratory, orthopedics, rehabilitation.

The disease occurs in children who have received two mutated versions of the involved chromosome from their parents. It can therefore appear in children whose two parents each carry a mutated chromosome, but who are healthy carriers and are completely unaware of it. “I had a cousin pass away from SMA and my niece wasn't developing like any other baby. My sister learned that her daughter had SMA, says Flavia, Ibrahima's mother. She then arranged for prevention in the family so that we could do genetic testing. We did this test with my partner, and we were both carriers. » Upon learning that their unborn child was affected, “we decided to continue the pregnancy while maintaining hope for him. We subsequently learned that gene therapy existed. It’s the best choice we made for him,” says Flavia.

Ibrahima was more fortunate than her cousin: when he was barely 5 weeks old, before the appearance of symptoms, the baby was able to receive gene therapy, the development of which was financed by the Telethon, all as was the discovery of the gene in question in 1995. Since then, more than 100 children have been treated in France, and more than 3,000 worldwide. The challenge now is to detect the disease as early as possible and the AFM-Téléthon has launched a pilot neonatal screening study in two regions, the Grand Est and Nouvelle Aquitaine. Four babies have been treated since the start of the year following this early detection. “How can we not think of all the others, of these children from other regions?” says Laurence Tiennot-Herment, president of the AFM-telethon for 20 years.

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Samy, in his sixties, suffers from severe heart failure. He is also the first patient in a phase I clinical study, which aims to verify the safety of injecting “stem cell juice” to treat his heart failure. A study carried out at the Georges-Pompidou hospital in Paris, under the leadership of Professor Philippe Ménasché, supported by the AFM-Téléthon because “the heart muscle is particularly affected in certain neuromuscular diseases”, indicates the association in its press kit. “I received three injections. I immediately felt the improvement, testifies Samy. I felt really better every day... Today I feel in good shape.” In France, more than 1.5 million people suffer from heart failure, particularly those over 60. It causes 200,000 hospitalizations per year and according to health insurance, its frequency will increase by 25% every 4 years following the aging of the population.

In 2018, Professor Philippe Menasché and his team from the cardio-muscular department at the European Georges Pompidou Hospital (AP-HP) successfully carried out the first transplant of muscle stem cells into the heart for patients with heart failure. The team found that it is the active ingredients contained in cells called “secretome”, and not whole cells, which improve heart function. The team then decided to extract this secretome, renamed “cell juice”. Injected venously, the product “improves the healing of certain tissues (liver, kidneys, spleen, heart), they create signals in the heart of the animal tested and improve the function of the organs”, reports Professor Albert Hagège, cardiologist in Professor Menasché's team at the Georges Pompidou hospital.

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European feat! “A week after the injection, my complexion became pink again, I was no longer yellow and my bilirubin level started to drop,” testifies Stefania, treated in June 2021 with gene therapy against Crigler-Najjar syndrome. It is a recessive genetic disease that affects the gene for a hepatic (liver) enzyme and causes the accumulation of bilirubin in the body. The manifestations are jaundice (yellowish discoloration of the skin, the back of the eye and the mucous membranes). The disease can progress to kernicterus, an accumulation of bilirubin in the brain causing neurological disorders leading to death. This disease manifests itself at birth and affects fewer than 20 people in France to date. Treatment involves intensive phototherapy: patients must spend 6 to 12 hours a day under LED lamps. It’s relatively easy for toddlers, “but for children, adolescents and adults, it’s restrictive. Liver transplantation to restore the activity of the enzyme is limited by the number of donors and the use of lifelong immunosuppressants,” explains Giuseppe Ronzitti, researcher at Inserm and Généthon.

His team has developed a new gene therapy, which involves delivering the faulty gene to the patient's liver cells. “The treatment is well tolerated, it allows the level of the enzyme to be restored and phototherapy to be stopped. It avoids transplantation,” reports Giuseppe Ronzitti. The scientific results published in the New England Journal of Medicine are impressive: patients treated at the highest dose can do without phototherapy after 16 weeks, and 80 weeks after the injection the bilirubin level is still low without phototherapy.

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Despite these successes, the work that remains to be done remains immense: 95% of rare diseases remain without treatment, or even without a reliable and precise diagnosis. Margaux, 26, suffering from limb-girdle myopathy, says she lives “with pain. I'm still walking, but I'm not working at 100%, it's mentally tiring. Léon, 10 years old, suffers from giant axon neuropathy, a disease of the nerves and muscles which gradually deprives its victims of movement before reaching the nervous system. Ivy, 4 years old, suffers from an as yet unidentified myopathy and her parents unfortunately see their little girl's condition deteriorating.

As Vianney, sponsor of the 2023 Telethon, sings, “It’s not just genes that make families, humans who love each other are enough, and if the downpour hits us, you and me, we go through it together, three ". But loving each other is not enough when it comes to genetic diseases, and the Telethon is above all the story of a citizen collective where patients, families, researchers and doctors get involved. For Serge Braun, scientific director of the AFM-Téléthon, “research needs to provide knowledge and therapeutic avenues. We must support research laboratories in France and abroad.” Will you be part of the adventure this year by donating to 36.37, or on the website www.afm-telethon.fr?