AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model

• Published in: EMBO molecular medicine 2022-05, Vol.14 (5), p.e14649-n/a
• Main Authors: Habbas, Karima, Cakil, Oktay, Zámbó, Boglárka, Tabet, Ricardos, Riet, Fabrice, Dembele, Doulaye, Mandel, Jean‐Louis, Hocquemiller, Michaël, Laufer, Ralph, Piguet, Françoise, Moine, Hervé
• Format: Article
• Language: English
• Subjects: AAV; Animals; Behavior; Brain; Diacylglycerol kinase; Diacylglycerol Kinase - genetics; Diacylglycerol Kinase - metabolism; Disease Models, Animal; EMBO16; EMBO27; FMR1 protein; Fmr1‐KO; FMRP; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - therapy; Gene therapy; Homeostasis; Intellectual disabilities; Kinases; Life Sciences; Mice; Mice, Knockout; Morphology; mRNA; Neurons; Phenotypes; Phosphatidic acid; Plasmids; Protein synthesis; Proteins; RNA-binding protein
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114649

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1 ‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1 ‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS. Synopsis Brain neuron‐restricted expression of an FMRP‐independent DGKk enzyme via intra‐cerebral adeno‐associated virus (AAV) gene therapy corrects phosphatidic acid deficiency and rescues disease relevant behavioral phenotypic alterations in a mouse model of Fragile X syndrome (FXS). The expression of diacylglycerol kinase kappa (DGKk), a favored mRNA target of FMRP, is reduced in the FXS brain in both humans and mice. ∆N‐DGKk is a truncated active enzyme whose synthesis bypasses the need for FMRP. AAV‐Rh10‐∆N‐DGKk enables the synthesis of active DGKk enzyme in neurons lacking FMRP. ∆N‐DGKk neuronal expression has no adverse effect in wild type control mice and is associated with normal behavioral functions of the rescued Fmr1 ‐null mice. Graphical Abstract Brain neuron‐restricted expression of an FMRP‐independent DGKk enzyme via intra‐cerebral adeno‐associated virus (AAV) gene therapy corrects phosphatidic acid deficiency and rescues disease relevant behavioral phenotypic alterations in a mouse model of Fragile X syndrome (FXS).