Gene therapy for neurodegenerative disorders in children: dreams and realities.

Gene therapy encompasses the administration of biological medicinal products containing recombinant nucleic acids, mainly DNA, with the aim of treating or curing diseases. This represents a unique therapeutic strategy to reach the brain, in order to prevent or halt a neurodegenerative process. During the past decade, active multidisciplinary research has started to solve many issues for gene therapy in neurodegenerative disorders in terms of vectors, modes of administration, and expression of the therapeutic DNA. The engineering of hematopoietic stem cells (HSC) with lentivirus vectors for ex vivo gene therapy has demonstrated efficiency in reaching the brain through their transformation into microglial/macrophages cells with a long-term gene expression of the therapeutic vector as an alternative to autologous HSC transplants. Two drugs based on this strategy have been approved to date. The first is for metachromatic leukodystrophy (MLD), a severe lysosomal storage disease, and provides high levels of the deficient enzyme; the second one is for cerebral forms of X-linked adrenoleukodystrophy (X-ALD), and works by halting the neuroinflammation process. However, due to the long-lasting effect of the procedure, the therapy is applicable only to pre- or pauci/oligo-symptomatic patients. In vivo gene therapy via direct injection into the brain or the cerebrospinal fluid, but also by intravenous injection, represents a more efficient approach; however, many challenges remain to be solved despite the approval of two drugs: one for the early infantile form of spinal muscular atrophy (SMA), in which the gene product injected intravenously is able to prevent spinal motoneuron neurodegeneration. The second one, for aromatic L-amino acid decarboxylase (AADC) deficiency, provides the defective enzyme to the basal ganglia via intraparenchymal injection. The production of vectors able to reach the brain target cells with a sufficiently high expression remains a major bottleneck. In parallel, efforts must continue in order to better define (i) the natural history and clinical outcomes of many neurodegenerative disorders with childhood onset, and (ii) the mechanisms involved in the neurodegenerative process. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.