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Use of PTX-BD4-3, a small molecule that activates a protein receptor involved in a pathway that appears to be altered in Rett syndrome, improved motor and respiratory function in a mouse model of the disease, study finds .
These results support further studies to better characterize PTX-BD4-3, possibly paving the way for clinical trials in Rett patients, its investigators said.
The study, “Restoration of motor learning in a mouse model of Rett syndrome after long-term treatment with a novel small molecule activator of TrkB, ”Was published in the journal Models and mechanisms of the disease.
Rett syndrome is mainly caused by the lack of the functional form of a protein called MeCP2, which is responsible for controlling the activity of other genes, as well as maintaining synapses (the sites where nerve cells communicate. ).
One of the consequences of a working MeCP2 deficiency is the disruption of a signaling pathway that involves the protein receptor known as tropomyosin receptor kinase B (TrkB) and its ligand, called neurotrophic factor derived from brain (BDNF), which is believed to contribute to some of the neurological problems seen in patients.
This is believed to be mediated by two independent mechanisms, in which the absence of the MeCP2 protein gradually lowers BDNF levels and excessively activates a gene that promotes TrkB inactivation.
Previous research has found that increasing BDNF levels and / or activating TrkB in Rett mouse models can attenuate or reverse neurological alterations that mimic disease symptoms.
Researchers at Case Western Reserve University School of Medicine and colleagues at Stanford University School of Medicine explored the therapeutic potential of PTX-BD4-3, a new small molecule, in a Rett mouse model.
Using cells grown in the lab, the researchers showed that PTX-BD4-3 specifically activated TrkB. They also demonstrated that the new compound promoted nerve cell survival, indicating that PTX-BD4-3 was able to induce biologically relevant responses associated with TrkB activation.
Further work has shown that the compound was able to trigger TrkB activation when injected into the abdomen of male mice genetically engineered not to produce the MeCP2 protein.
The experiments also indicated that PTX-BD4-3 was rapidly cleared from the brain and bloodstream of animals after administration, with a half-life of approximately two hours. (Half-life refers to the time it takes for the levels of a compound circulating in the body to drop by half.)
Investigators then focused on evaluating the ability of PTX-BD4-3 to alleviate certain symptoms typical of Rett in a mouse model. They treated female mice lacking a copy of the gene that encodes MeCP2 with low dose PTX-BD4-3 (5 mg / kg) once every three days, for a total of eight weeks.
Respiratory and motor function tests performed during treatment showed that PTX-BD4-3 reduced symptoms of apnea (breathing pauses) and promoted motor learning in response to a balance and motor coordination test performed. on a rotating rod. These improvements were maintained for at least a day after administration.
“The present results demonstrate that a chronic low dose intermittent treatment paradigm targeting the neurotrophin TrkB receptor can produce a significant and clinically relevant symptomatic benefit in a murine model of RTT [Rett]The researchers wrote.
They added that these results indicate that “PTX-BD4-3 may be considered a candidate for further characterization, including formal studies of new investigational drugs for potential clinical trials, in the context of RTT.”