New drug candidates could aid treatment of Rett syndrome

Written by Alice Weatherston

Recent research carried out at Cold Spring Harbor Laboratory (NY, USA) has indicated that the lifespan of male mice models of Rett syndrome can be significantly extended through the use of small-molecule drug candidates. The research, which was published in the Journal of Clinical Investigation, could inform a new approach for the treatment of the disease.
“At this time, there is no disease-modifying therapy for Rett syndrome,” lead author Nicholas Tonks (Cold Spring Harbor Laboratory) explained, “and the focus of most current therapies is management of symptoms. Our approach represents a new strategy.”

Work carried out across 25 years by Tonks and his team has previously highlighted the relevance of the enzyme, termed PTP1B, as a key player in the control of signaling cascades for processes such as growth and metabolism. Identifying that metabolic regulation is abnormal in Rett syndrome and that PTP1B levels were notably high in model mice, Navasona Krishnan (Cold Spring Harbor Laboratory) hypothesized that inhibitors of PTP1B may be able to have some effect on addressing the symptoms of the disease.

Results indicated that in male mice models of Rett syndrome, one of the PTP1B inhibitors developed by the team (CPT157633) extended median lifespan from 50 days to ~75 days, another (UA0713) raised survival to 90 days.

In addition to this, in more mature model female mice, PTP1B inhibitors were shown to improve behavioral symptoms. For example, paw-clasping behaviour was reduced from nearly 100% to 25% and in a walking test, model mice could remain on a rotating wheel for significantly longer than untreated mice following PTP1B inhibitor administration.

The mechanism underlying these improvements was attributed to a link between PTP1B and the neural growth factor termed BDNF, which is critical in early brain development and later functioning.

“Under normal conditions, PTP1B levels are low and signaling via TRKB [cell receptors] is promoted. In Rett syndrome, PTP1B levels are extremely high and signaling through TRKB is attenuated. When you inhibit PTP1B, as our drug candidates do, you restore BDNF signaling through the TRKB receptor,” explained Tonks.

The team have now set up new collaborations with expert Rett syndrome labs to continue to ascertain the potential efficacy of the inhibition of PTP1B in controlling the varied symptoms of the disorder.

Source: Cold Spring Harbor Laboratory press release