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First in vivo success of a gene therapy for the maple syrup urine disease

In a new study published in Nature Communications, teams coordinated by Prof. Manuel Schiff and Dr. Clément Pontoizeau, within the rare disease department and reference centre for hereditary metabolic diseases at the Hôpital Necker-Enfants Malades AP-HP and the research laboratory for the genetics of mitochondrial diseases, directed by Agnès Rötig, at the Institut Imagine (Inserm, APHP, Université Paris Cité), with the collaboration of the rAAV plateform coordinated by Marcelo Simon-Sola, have successfully tested a gene therapy on mouse models of leukinosis, or maple syrup urine disease, a rare and severe genetic metabolic disease. This is a first key step towards the development of treatment in humans. This research is financed by the DIM Gene Therapy (Major Interest Area) coordinated by Prof. Marina Cavazzana.

Maple syrup urine disease (MSUD) is an inherited metabolic disease. It affects about 150 patients in France, 500 in Europe, and 500 in North America. Ultra rare and poorly understood, maple syrup urine disease (MSUD) is extremely serious if left untreated. It is due to a defect in the leucine transformation process, leading to brain and body intoxication by this amino acid and its derivatives. It manifests itself in the days following birth by a coma and the need for dialysis and resuscitation care. Today, existing treatments are restrictive, affecting the quality of life of patients and must be followed throughout their lives. Even with a strict, extremely low-protein diet, the patient is still at risk of severe neurological manifestations and coma, especially in high-risk situations such as infection, prolonged fasting, or diet deviation.

In order to cure patients in the long term, teams from the rare disease department and reference centre for hereditary metabolic diseases at the Hôpital Necker-Enfants Malades AP-HP and from the genetics of mitochondrial diseases research laboratory, directed by Agnès Rötig, at the Institut Imagine, are working on the implementation of a gene therapy for maple syrup urine disease (MSUD). For the first time, they have successfully tested it in vivo in mice. Their results have just been published in the journal Nature Communications [1].

Very encouraging results from a new gene therapy approach

“We have developed a gene therapy to cure mice with maple syrup urine disease (MSUD) using a gene as a drug,” explains Prof. Manuel Schiff, a paediatrician at the Reference Centre for Inherited Metabolic Diseases at the Necker-Enfants Malades Hospital and a researcher at the Institut Imagine, in the laboratory of genetics of mitochondrial diseases. To do this, the researchers used a vector (called AAV8) produced at the Institut Imagine by the rAAV plateform, directed by Marcelo Simon-Sola, and into which the healthy gene of interest is introduced. “Mice with maple syrup urine disease (MSUD) showed clinical signs equivalent to humans, with early death, significant growth retardation and the same biochemical markers of intoxication in the blood,” explains Dr Clément Pontoizeau, a medical biologist and researcher at the reference centre and laboratory. After intravenous injection of the vector containing the healthy gene, immediately after birth, the researchers observed an improvement in all the clinical and biological parameters: “the animals appear cured, show no symptoms, excellent correction of biochemical markers, normal weight and behaviour, in a sustainable manner,” adds Manuel Schiff.

A proof of concept to be developed

This research represents a decisive step and opens up real prospects for future treatment in patients. After this proof of concept, there are still many steps to be taken before this approach can be tested in humans. These include proving the safety of the vector and optimising it to ensure that it reaches the right place in the body. Further experiments in animal models closer to humans will be carried out, in collaboration with specialised teams, in the hope of applying this gene therapy in the relatively near future. Another long-term objective, dear to the teams, would be to be able to use this approach in other hereditary metabolic diseases.


[1] C. Pontoizeau et al., Nature Communications, 2022