Small Molecule Aids Motor Skills, Breathing in Rett Mouse Model

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by Joana Carvalho |

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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 impaired in Rett syndrome, improved motor and respiratory function in a mouse model of the disease, a study found.

These findings support further studies to better characterize PTX-BD4-3, possibly preparing the way for clinical trials in Rett patients, its investigators said.

The study, “Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel small-molecule activator of TrkB,” was published in the journal Disease Models & Mechanisms.

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 shortfall is the 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 lack of the MeCP2 protein gradually lowers BDNF levels and overly activates a gene that promotes TrkB inactivation.

Prior research found that increasing BDNF levels and/or activating TrkB in mouse models of Rett can ease 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 new small molecule, in a mouse model of Rett.

Using lab-grown cells, the investigators 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 showed the compound was able to trigger TrkB activation when injected into the abdomen of male mice genetically modified to not produce the MeCP2 protein.

Experiments also indicated PTX-BD4-3 was rapidly eliminated from the animals’ brain and bloodstream following administration, with a half-life of around two hours. (Half-life refers to the time it takes for the levels of a compound circulating in the body to drop by half.)

The investigators then focused on assessing whether PTX-BD4-3 might be able to alleviate some typical Rett symptoms in a mouse model. They treated female mice lacking one copy of the gene that encodes MeCP2 with PTX-BD4-3 at low dose (5 mg/kg) once every three days, for a total of eight weeks.

Respiratory and motor function tests performed over the course of treatment showed that PTX-BD4-3 reduced apnea symptoms (breathing pauses), and promoted motor learning in response to a balance and motor coordination test done on a rotating rod. These improvements were maintained for at least one day following dosing.

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

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