Fragile X Syndrome is one of the most common inherited neurodevelopmental disorders characterized by developmental and synaptic function impairment. Advantx‘s candidate ADV127 has been precisely designed to bind Sigma-1 receptors to restore key signaling pathways and stimulate neuronal homeostasis.
Fragile X Syndrome
Fragile X Syndrome is a rare genetic disorder caused by changes in the FMR1 gene on the X chromosome, leading to atypical gene methylation and transcriptional silencing with the consequent reduction in the synthesis of the mental retardation protein (FMRP). The FMRP is an RNA binding protein needed for brain development, including the decreased expression of brain-derived neurotrophic factor (BDNF), which affects the same time expression of Fmr1. Levels of FMRP correlate with the overall severity of the FXS phenotype, with males being more severely affected due to the X-linked pattern of the disorder. Individuals with FXS are at increased risk of cognitive impairment, characteristic physical features, and behavioral abnormalities such as anxiety, hyperarousal, attention-deficit/hyperactivity disorder features, self-injurious behavior, aggression, irritability, and stereotypic and perseverative behavior. Also, a large proportion of individuals with FXS display autistic features.
The Sigma-1 receptor is a key modulator of calcium signaling from the endoplasmic reticulum to the mitochondria regulating synaptic processes such as firing rate setpoint and homeostatic synaptic plasticity which are altered in FXS. Sigma-1 also plays a role in correcting impaired autophagy and protein homeostasis, and restores neurite and astrocytes formation, synaptic plasticity, and presynaptic differentiation connected to the alteration of the BDNF pathway in FXS.
Potential market for Advantx candidate in Fragile X syndrome
Prevalence>30k people in US/EU/UK/JP
Treated Population>20k patients
Market Growthest. 5.4% CAGR
data from Globaldata
Fragile X Syndrome and RETT Syndrome, different Etiology With Common Molecular Dysfunctions
FRAGILE X SYNDROME
Fragile X Syndrome (FXS) is a genetic disorder caused by the silencing of the Fragile X Mental Retardation gene 1 (FMR1), and its encoded protein, the Fragile X Mental Retardation Protein (FMRP) is not expressed. FMRP is an RNA-binding protein and a component of ribonucleoprotein complexes involved in shuttling between nucleus and cytoplasm, transport along dendrites, and association to polyribosomes. The frequency of the brain waves is also affected in FXS.
The symptoms in male patients with FXS are more severe than in females and include developmental delays and behavioral and social deficits. FXS patients may show some degree of intellectual disabilities, while females may have normal intelligence to mild intellectual disability.
Fragile X syndrome affects one in every 4000 males and one in every 7000 females.
Rett Syndrome (RTT) is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 is expressed mostly in the brain, and it is an important regulator in brain development. Its altered functionality leads to neurodevelopmental deficits including impaired modulation of brain cell connectivity.
MeCP2 and FMRP, despite differences in genetic etiology, present overlapping features in RTT and FXS by the common influence of the expression of brain-derived neurotrophic factor (BDNF).
Patients with RTT show apparent normal development up until 18 months, after which there is a regression in motor and language skills accompanied to behavioral and autonomic deficits. The majority of patients with RTT are females with a prevalence of one in every 10,000 births.
ADV127 FXS is Advantx’s candidate for the treatment of Fragile X Syndrome and the basis for a future development for Rett syndrome.