Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

With $349,000 in funding from FRAXA Research Foundation from 2008-2015, Dr. Paul Lombroso and his team at Yale University researched if inhibiting STEP could reduce behavioral abnormalities in Fragile X syndrome. Results published.

Results Published: STEP inhibition reverses behavioral, electrophysiologic, and synaptic abnormalities in Fmr1 KO mice
Paul Lombroso, PhD, Yale University, FRAXA Investigator
$349,000 Grant
Paul Lombroso, MD
Principal Investigator

Manavi Chatterjee, PhD
FRAXA Postdoctoral Fellow (2014-2015)

Susan Goebel Goody, PhD
FRAXA Postdoctoral Fellow (2009-2012)

Deepa Venkitaramani, PhD
FRAXA Postdoctoral Fellow (2008)

Yale University Child Study Center
2014-2015 FRAXA Research Grant
$259,000 over 4 Years (2008-2011)

2014: A Novel STEP inhibitor

by Paul Lombroso

We are using a newly identified pharmacological inhibitor of STEP to reduce behavioral abnormalities in Fragile X mice. We identified TC-2153 as a novel STEP inhibitor which can cross the blood brain barrier and inhibits STEP in normal (wildtype) mice. We will administer TC-2153 to adult Fragile X mice to determine whether pharmacologic inhibition of STEP reduces FXS-related deficits. This work will assess the disease modifying potential for STEP inhibitors in FXS and validate STEP as a target of drug discovery.

Genes Brain Behav. 2012; Genetic manipulation of STEP reverses behavioral abnormalities in a Fragile X syndrome mouse model.
Goebel-Goody SM1, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ.

After several years as a FRAXA Postdoctoral Fellow in Dr. Lombroso’s lab, Dr. Goebel-Goody won international recognition for her work at the 2011 Society for Neuroscience Annual Meeting in Washington, D.C., where she was selected as one of 50 out of 16,000 presenters to discuss her findings at a ‘Hot Topics’ in neuroscience press conference. 

Dr. Susan Goebel-Goody completed her studies in Dr. Lombroso’s lab in 2012, and she went on to work for Pfizer in drug development.

There are at least three major pharmaceutical companies which have identified STEP in their drug development pipeline.

Mind Your STEP Levels: Validation of a New Drug Target in Fragile X

by Susan Goebel-Goody, PhD, 9/4/2012

A priority of FXS research is to discover mRNAs that are regulated by FMRP, the protein that is functionally absent in FXS, since these are potential therapeutic targets.

Our team is testing the hypothesis that reducing and/or inhibiting STriatal-Enriched tyrosine Phosphatase (STEP) rescues some of the deficits present in the mouse model for FXS. STEP is located in neurons at the synapse, the structure permitting communication between neurons. The synapse is highly plastic and strengthens or weakens in response to stimuli from other neurons. STEP opposes synaptic strengthening and promotes synaptic depression by facilitating internalization of the AMPA receptor subtype of glutamate receptors.

Normally, FMRP binds to STEP mRNA and suppresses its translation into protein. As a result, STEP protein is elevated in FXS in absence of functional FMRP. Increased levels of STEP protein may therefore contribute to the weakening of synaptic connections in FXS.

Using a genetic approach to eliminate STEP levels in FXS mice, we have exciting data which demonstrates that loss of STEP renders FXS mice less susceptible to audiogenic seizures. This data validated STEP as a target for drug discovery, and we have obtained a STEP compound inhibitor from an initial screen of 150,000 compounds. Our proposal will examine whether genetically reducing STEP protein levels and/or pharmacologically inhibiting STEP activity reverses the anxiety, cognitive, and socialization deficits present in FXS mice. We will also determine if reducing STEP levels and/or activity reverses the exaggerated metabotropic glutamate receptor-dependent long term depression found in FXS mice.

Investigating the role of STEP in FXS addresses a key unanswered question in FXS research with clear therapeutic implications. Namely, it links over-expression of STEP with the enhanced AMPA receptor internalization and exaggerated long term depression present in FXS mice. This work has tremendous therapeutic potential for patients with FXS since pharmaceuticals targeting STEP could be developed. Moreover, given that FXS remains the most inherited form of autism, results from this study could have broader implications in the treatment of autism and other related disorders.

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Global Leader in Fragile X Research

FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.

Explore Current Research Grants
Help Fund the Cure