Targeting ERK and mTOR for the treatment of fragile X syndrome

Neurodevelopmental disorders such as fragile X syndrome (FXS) are significantly disruptive to affected individuals and their families. Early deficits that impact attention, learning, social interaction are not only disabling in themselves, but may also preclude normal environmental experiences, thus further perturbing experience-dependent brain development. Therefore, there is growing interest in addressing not only the symptoms of these disorders but also their underlying neurobiological causes.

Our proposal is based on the observations that two well-studied signalling pathways may be involved in FXS pathogenesis: the ERK pathway and the mTOR pathway. Both of these pathways are potential drug targets and may be modulated by some commonly used drugs. Our goal is to test the potential efficacy and safety of modulating these pathways using pharmacological or genetic means in a FXS mouse model. If successful, these studies will provide fast and direct applications to clinical trials in patients and will also help select patients with neurodevelopmental disabilities that may benefit from these and related treatments.

With the proposal of the metabotropic glutamate receptor (mGluR) theory of fragile X syndrome, new targeted treatment strategies are being tested for fragile X syndrome (FXS), most notably mGluR5 inhibitors. It is believed that the therapeutic benefit of mGluR5 antagonism is accomplished by normalizing synaptic protein synthesis, which is elevated in FXS. However, mGluR5 receptors activate many signaling cascades that are unrelated to protein synthesis regulation, so a serious concern is that mGluR5 inhibitors will have side effects that limit their utility. It is therefore important to know if the selective targeting of intracellular signaling pathways is a viable alternative.

Our previous work strongly suggests two pathways that control mRNA translation as potential treatment targets in FXS: the extracellular signal related kinase 1/2 (ERK) pathway and the mammalian target of rapamycin (mTOR) pathway. In the current proposal, we will test the validity of these pathways as targets for the treatment of FXS by investigating anatomical, electrophysiological, and systems level phenotypes in the FXS mouse model (Fmr1-/y). In Specific Aim 1, the effects of ERK inhibition will be assessed using lovastatin, a statin that is already in widespread clinical use for hypercholesterolemia in adults and children, which we previously showed reduces ERK activation and corrects epileptogenic phenotypes in the Fmr1-/y. In Specific Aim 2, the effects of mTOR enhacement will be tested by genetic reduction of the mTOR pathway suppressor protein TSC2. We previously showed that genetic reduction of Tsc2 resolves two hippocampal phenotypes in the Fmr1-/y, and we now propose to use the same strategy to broadly define the role of mTOR enhancement for the treatment of FXS.

Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability (ID), one of the most common single-gene causes of autism spectrum disorder (ASD). In recent years, much has been learned about the genetics of neurodevelopmental disorders such as FXS, yet there remains a profound lack of treatments that target the underlying pathophysiology. This proposal addresses the urgent need for better pharmacological strategies for treating FXS and related neurodevelopmental disorders.

The beneficiaries of the proposed research are many. Identification of new treatment strategies for FXS and potentially other ASD/ID will relieve the burden on affected individuals and their families. Our results will be of significant value to clinical practitioners who design clinical trials, and who treat patients with FXS. The pharmaceutical industry will benefit from our findings by considering new therapies based on our results, and designing new drugs that can target the ERK and mTOR pathways. We expect that the timescale of the translation of our results will be within the realm of years, as lovastatin is already available for use in adults and children.

It is estimated that the prevalence of ASD/ID in the UK is approximately 1%, and this results in significant costs necessary to care for affected individuals. The development of new treatments will thus relieve the government of a significant financial burden. Additionally, the University will benefit from this research if it results in new patents that generate revenue. As evidence of this, my previous research has generated a patent that is partially owned by MIT (see CV). The high-impact papers based on this research will also raise the academic and scientific profile of the University and UK research. Our research will also benefit charities devoted to the treatment of FXS and ASD/ID by validating the value of the scientific research they support. Finally, the postdoctoral researcher and any Ph.D. or Masters students working on this project will benefit from training in multiple neuroscience techniques, and the exposure to cutting-edge research performed in the Edinburgh Neuroscience community.