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Small molecule aids motor skills, breathing in Rett mouse model

Use of PTX-BD4-3, a small molecule that activates a protein receptor involved in a pathway that appears to be impaired in Rett syndrome, improved motor and respiratory functions in a mouse model of the disease, study finds .

These results support further studies to better characterize PTX-BD4-3, perhaps 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 TrkB activatorwas published in the journal Disease models and mechanisms.

Rett syndrome is mainly caused by the absence 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 functional MeCP2 deficiency is disruption of a signaling pathway that involves the protein receptor known as tropomyosin receptor kinase B (TrkB) and its ligand, called brain-derived neurotrophic factor. (BDNF), which is thought to contribute to some of the neurological problems seen in patients.

This is thought to be mediated by two independent mechanisms, in which the absence of the MeCP2 protein progressively lowers BDNF levels and over-activates a gene that promotes TrkB inactivation.

Previous research has shown that increasing BDNF levels and/or activating TrkB in mouse models of Rett can attenuate or reverse neurological alterations that mimic disease symptoms.

Researchers at Case Western Reserve University School of Medicine with colleagues at Stanford University School of Medicine explored the therapeutic potential of PTX-BD4-3, a novel small molecule, in a mouse model of Rett.

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.

Other work showed that the compound was able to trigger the activation of TrkB when injected into the abdomen of male mice genetically modified not to produce the MeCP2 protein.

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 levels of a compound circulating in the body to drop by half.)

The researchers then focused on evaluating the ability of PTX-BD4-3 to alleviate certain typical Rett symptoms 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 (pauses in breathing) 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 one day after administration.

“The present results demonstrate that a low-dose chronic intermittent treatment paradigm targeting the TrkB neurotrophin receptor can provide significant and clinically relevant symptomatic benefit in a mouse model of RTT. [Rett]“, wrote the researchers.

They added that these results indicate that “PTX-BD4-3 may be considered a candidate for further characterization, including formal studies of investigational new drugs for potential clinical trials, in the context of RTT.”

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