Glix 13, a New Drug Acting on Glutamatergic Pathways in Children and Animal Models of Autism Spectrum Disorders

Abstract

Recently standardized diagnostic instruments have been developed in diagnostic and therapeutic procedures for Autism Spectrumv Disorders (ASD). According to the DSM-5 criteria, individuals with ASD must show symptoms from early childhood. These symptoms are communication deficits and restricted, repetitive patterns of behaviour. It was recently described by Bioinformatic analysis that 99 modified genes were associated with human autism. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor gene family was identified among these. Using ultrasonic vocalizations, it was demonstrated that genetic variation has a direct impact on the expression of social interactions. It has been proposed that specific alleles interact with a social reward process in the adolescent mouse modifying their social interaction and their approach toward each other. In this review we report that the monoclonal antibody-derived tetrapeptide GLYX-13 was found to act as an N-methyl-D-aspartate receptor modulator and possesses the ability to readily cross the blood brain barrier. Treatment with the NMDAR glycine site partial agonist GLYX-13 rescued the deficit in the animal model. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism in autistic children.

Autism throughout genetics: Perusal of the implication of ion channels

“…As a matter of fact, the authors concluded that B6B21 acts in a similar way to glycine on the receptor (Haring, Stanton, Scheideler, & Moskal, 1991). From B6B21, derived a family of small peptides called glyxines (Santini et al., 2014). One of these peptides, named GLYX‐13, was found to modulate NMDAR properties in a similar way to glycine.…”

“…Treating ASD‐affected rats with of GLYX‐13 resulted in promising improvements of autistic signs. Thereafter, authors suggested that this antibody might be a potential treatment for patients affected by ASD (Santini et al., 2014). Moreover, d ‐cycloserine, which is a partial NMDAR glycine agonist, is known to have effects on the behavioral deficits observed in autism and schizophrenia (Posey et al., 2004).…”

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice

“…Numerous studies have shown that enhancing NMDAR function, via activation of glycine binding site or modulation of metabotropic glutamate receptors, represents a promising approach to reverse psychotomimetic effects of ketamine (Chan et al, 2008;Krystal et al, 2005;Roberts et al, 2010;Yang et al, 2010) or other NMDAR antagonists (Kanahara et al, 2008;Kawaura et al, 2015;Le Pen et al, 2003;Lipina et al, 2005;Santini et al, 2014;Shimazaki et al, 2010). On the other hand, facilitation of NMDAR-mediated transmission via direct activation of NMDAR glycine site or inhibition of the glycine transporter 1, such as GLYX-13, D-cycloserine, and sarcosine, has shown potential benefits in treatment of major depression (Burgdorf et al, 2013;Huang et al, 2013;Karcz-Kubicha et al, 1999;Papp and Moryl, 1996).…”

Pharmacogenomic Medicine in Autism: Challenges and Opportunities

“…There is limited, yet promising, evidence for the development of novel compounds with therapeutic targets for core symptoms of ASD. For example, recent preclinical studies have suggested that a few therapeutic targets in ASD, such as the glutamatergic pathway, can be modulated by novel compounds such as the N-methyl-D-aspartate (NMDA) receptor glycine-site partial agonist GLYX-13 [1,2]. Additionally, neuroligin-3 knockout mice (a model for nonsyndromic ASD) may exhibit disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor-dependent synaptic plasticity.…”