Fragile X syndrome (FXS) represents the most common form of inherited cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorder. As a result of a trinucleotide (CGG) expansion, the FMR1 gene is silenced and makes little or no FMR1 protein (FMRP). FMRP is an RNA-binding protein that negatively regulates protein synthesis. The loss of FMRP causes neurodevelopmental deficits and alterations in cerebral metabolism. ACT01 is a novel precision small molecule candidate drug inhibiting only the activity of dopamine transporter. In behavioral studies, administration of ACT01 restored phenotype behaviors of FMR1-null animals back to their wild type littermates. The outcomes of these experiments for the first time substantiate the possible links of abnormal behavior phenotypes, to reduced extracellular dopamine or dopamine deficiency, to excessive dopamine transporter activity, and to abnormal metabolism. These outcomes further suggest that ACT01 is a viable therapeutic candidate for FXS. DRI Biosciences intends to develop ACT01 toward FXS clinical use.
The aim of the phase I proposal examines the effect of dopamine reuptake inhibition on 1) mediations of insulin secretion, 2) membrane protein presentation, and 3) the activities of the insulin signal transduction pathways. The entire body of research (Phase I/II) examines the effects (efficacy) of ACT01 on FXS pathophysiology and biochemistry, which will ultimately generate not only a useful medication but also a more relevant, translatable, and objective efficacy biomarker as an adjunct to the behavior assessments in human clinic.
Fragile X syndrome (FXS), a triple-?repeat (CGG) expansion disorder, represents the most common form of inherited cause of intellectual disability. The expansion of the triple-?repeat silences FMR1 expression and leads to the loss of FMRP, a repressor of protein synthesis (translation). Because of the loss of FMRP, XS is as much of a metabolic disorder as neurodevelopmental disorder. Elevated levels of cerebral glucose metabolism are noted in FMR1 null mice as well as in FXS patients. Elevated levels of cerebral glucose metabolism suggest elevated levels of insulin activity. High levels of insulin activate insulin receptors, which in turn activate a chain of other enzymes. The end result of all this increased activity is the excessive expression of dopamine transporter protein within the cell membrane or on the cell surface. The more transporter protein present on the cell surface, the less extracellular dopamine is present. Excess transporter proteins act to mop up extracellular dopamine. Dopamine must be present in extracellular space to deliver its primary signaling function. A protein called the dopamine transporter or the dopamine reuptake protein manages the amount or the duration of extracellular dopamine. Like an intake valve, the function of this protein is to absorb dopamine across the cell membrane from the surrounding extracellular neighborhood. Once brought inside the cell, dopamine is sequestered and is no longer functional. ACT01 is a novel precision small molecule candidate drug inhibiting only the activity of dopamine transporter. In behavioral studies, administration of ACT01 restored phenotype behaviors of FMR1-?null animals back to their wild type littermates. The outcomes of these experiments for the first time substantiate the possible links of abnormal behavior phenotypes, to DA deficiency, to excessive DA transporter activity, and to abnormal metabolism. These outcomes further suggest that ACT01 is a viable therapeutic candidate for FXS. DRI Biosciences intends to develop ACT01 toward FXS clinical use. The aim of the phase I proposal examines the effect of dopamine reuptake inhibition on 1) mediations of insulin secretion, 2) membrane protein presentation, and 3) the activities of the insulin signal transduction pathways. The entire body of research (Phase I/II) examines the effects (efficacy) of ACT01 on FXS pathophysiology and biochemistry, which will ultimately generate not only a useful medication but also a more relevant, translatable, and objective efficacy biomarker as an adjunct to the behavior assessments in human clinic.
