📰 A preclinical test of gene therapy concept for fragile X syndrome

Fragile X Syndrome (FXS) is the leading cause of familial intellectual disability for which there is currently no treatment. In this study published in the journal EMBO Molecular Medicinescientists are investigating the role ofenzyme (An enzyme is a molecule (protein or RNA in the case of ribozymes) that allows …) DGKk, deficient in this pathology (Pathology, term of the ancient Greek, is literally the speech, the …). They observe that the re-expression of this enzyme in mouse (The term mouse is an ambiguous vernacular name that can designate, for Francophones, before …) young adults correct their molecular alterations and major long-term behavioral disorders. These results support an important role of DGKk enzyme dysfunction in this pathology.


© Hervé Moine

the syndrome (A syndrome is a set of clinical signs and symptoms to which a patient is susceptible …) of Fragile X affects approximately one male (A man is an adult male individual of the species called Modern Man (Homo …) in 4000 women and one in 8000. This syndrome is caused by a mutation in the embarrassed (A gene is a deoxyribonucleic acid (DNA) sequence that specifies the …) FMR1, located at X chromosome (The X chromosome is one of two sex chromosomes in humans and some animals …)which causes the loss of expression of the protein (A protein is a biological macromolecule made up of one or more …) FMRP. The latter is a protein that binds to RNA, the absence of which causes deregulation of the expression of many genes involved in communication (Communication affects both people (intrapsychic, interpersonal communication, etc.) between neurons in various regions of the brain (The brain is the main organ of the animal’s central nervous system. The brain processes …).

Previous work had identified the FMRP protein control (The word control can have several meanings. It can be used as a synonym for exam, of …) in neurons the production of a particular enzyme called kappa diacylglycerol kinase (DGKk). This enzyme could represent a key to the pathological mechanism because it is essential for the production of membrane lipids involved in intracellular signaling and for controlling the synthesis of new proteins necessary for neuronal communication.

Scientists tested the postulate that if the enzyme DGKk cheek (The cheek is the part of the face that covers the oral cavity, closed by …) an important role in the pathology, its re-expression in fragile “X” neurons could have the ability to correct their alterations. After identifying a modified form of the enzyme that it no longer has need (The needs are at the level of the interaction between the individual and the environment. It is …) of the FMRP protein to be produced in neurons, introduced the DGKk enzyme into the brain neurons of mouse pathology models using a vector (In mathematics, a vector is an element of a vector space, which allows …) adeno – associated virus (AAV), currently used in several trials of gene therapy (Gene therapy is a therapeutic strategy that involves doing …) in man. Treatment in young adult mice allows for a correction of molecular and behavioral abnormalities with a long-term effect (more than 8 weeks after treatment).

These results constitute a indication (An indication (from the Latin indicare: to indicate) is a piece of advice or a recommendation, written …) of the important role of this enzyme in the pathology and a first preclinical proof of concept of a treatment by approach of therapy (A therapy is a set of measures applied by a therapist to a …) there a stage (A stadium (from the ancient Greek στ? Διον stadion, from the verb …) young adult. He future (Futures is a science fiction collection from Aurora Editions.) Subsequent developments will require the development of a mode of vector administration applicable to humans and validations in other models.


The adeno-associated viral vector AAV-Rh10-∆N-DGKk, by allowing the re-expression of the deficient enzyme DGKk in Fmr1-KO mouse neurons, corrects the molecular and behavioral deficits of the preclinical model of fragile X syndrome. That strategy (Strategy – from the Greek stratos meaning “army” and ageîn meaning …), easier than acting directly on the FMRP protein, is a first preclinical proof of concept of a gene therapy approach in the young adult stage in mice. WT, “normal” mouse model; Fmr1-KO, “Fragile X” mouse model; DAG / PA, signaling of diacylglycerol lipids and acid (An acid is a chemical compound usually defined by its reactions …) phosphatidic.
© Hervé Moine

To find out more:

The diacylglycerol kinase DGKk provided by AAV achieves long-term rescue of the fragile X syndrome mouse model.
Habbas K, Cakil O, Zámbó B, Tabet R, Riet F, Dembele D, Mandel JL, Hocquemiller M, Laufer R, Piguet F, Moine H.
EMBO Mol Med. April 4, 2022 doi: 10.15252 / emmm.202114649.

Laboratories:
Institute of genetics (Genetics (from the Greek genno γεννώ = to give birth) is …) and of molecular biology (Molecular biology (sometimes abbreviated bio mol or BM) is a discipline …) and mobile – IGBMC (CNRS / Inserm / University of Strasbourg)
1 Street (The street is a traffic space in the city that serves homes and premises …) Laurent Fries. 87404 Ilkirch CEDEX.

Contact:
Hervé Moine – Director of research (Scientific research first designates all the actions carried out with the aim of …) CNRS (The National Center for Scientific Research, better known by its acronym CNRS, is the largest …) – monjo a igbmc.fr

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