Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

Abstract

Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT.

Zebrafish in understanding molecular pathophysiology, disease modeling, and developing effective treatments for Rett syndrome

“…Collectively, these comparative results of molecular genetics rodent and zebrafish models concerning human RTT patients confirm that the zebrafish RTT model will enable monitoring brain dynamics, neural morphology, muscle dysfunctions and behaviors through the entire normal life span of the organism 25,62,82,84,86 …”

Longitudinal Adaptive Behavioral Outcomes in Ogden Syndrome by Seizure Status and Therapeutic Intervention

“…Despite the difficulties involved in developing a vector able to cross the blood brain barrier can pose a challenge 74–77 , there are currently therapies being developed for other neurodevelopmental disorders. For example, gene therapies for mouse models and cell lines in Fragile X Syndrome 78 , Rett Syndrome 79 , Angelman Syndrome 80 , and others 81–84 have all completely or partially restored protein function. These results suggest that a restoration of function and improved adaptive behavioral outcomes over time are possible if implemented early enough.…”

A Natural History ofNAA15-related Neurodevelopmental Disorder Through Adolescence

“…Without insight into the later stages of the disorder, it will be more difficult for clinicians to help provide expectations of what to expect at different life stages to caregivers. NAA15-related neurodevelopmental disorder is thought to be caused by haploinsufficiency (Cheng et al, 2018; Tian et al, 2022) of which there are several therapies in development that show promise in cell lines and animal models that have been used in similar disorders such as Rett Syndrome and Angelman Syndrome to help restore protein function and dosage to adequate levels (Albadri et al, 2017; Burbano et al, 2022; Hill & Meisler, 2021; Milazzo et al, 2021; Palmieri et al, 2023; Protic et al, 2019). If interventions are implemented early enough, it may be possible to restore protein function and improve adaptive behavior skills.…”