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New Cardiff Research Group Aim to Develop Medications for Fragile X Syndrome

Updated: May 1, 2019

The recently-established Medicines Discovery Institute is based within Cardiff University and aims to translate the latest in scientific breakthroughs into novel drugs to treat patients, where there remains an unmet medical need.

Our new project

We recently received £2.5m from the Medical Research Council (which is essentially UK taxpayers) to fund an early stage drug discovery project for fragile X syndrome (FXS). Specifically, we will be aiming to identify a drug which interferes with the function of the protein, LIMK1, that is important for the development and function of brain cells. Emerging research suggests that processes involving this protein may be affected in FXS, leading to differences in brain development. Therefore, we are aiming to develop a drug to help to target these differences, in order to address some of the symptoms associated with Fragile X.

In this article we give an overview of the history of research aiming to develop medications and explaining in further detail our Fragile X work.

How are medications for brain-based disorders developed?

The History

In order to place our project into some kind of context, it is useful to consider the process by which drugs for treating disorders of the brain are identified and developed. The ‘first generation’ of drugs of the modern era, loosely defined as those identified in the 1940s, 50s and 60s, were introduced largely in the absence of any understanding of how either they or the brain itself worked. Nevertheless, drugs such as benzodiazepines (e.g. Valium) for the treatment of anxiety disorders and lithium for the treatment of bipolar disorder (or manic depression as it was then known) were major therapeutic advances with, for example, the first antipsychotic drug chlorpromazine being primarily responsible for rendering mental asylums obsolete.

With the recognition that brain function is dependent upon chemical communication between nerve cells, then in the 1970s, 80s and 90s a ‘second generation’ of drugs appeared which restored the imbalances in these chemicals, or neurotransmitters, that are responsible for a variety of different brain disorders. For instance, there is an imbalance of the so-called “mood chemical” serotonin in depression which is restored by selective serotonin reuptake inhibitors (SSRIs) such as Prozac. Likewise, in Alzheimer’s disease, the drug Aricept helps restore the imbalance in the neurotransmitter acetylcholine.


Research into brain function and the underlying biology of different conditions has now advanced to the point where, for certain disorders, we can begin to understand the mechanisms that cause the chemical imbalances and/or the changes in brain structure and function that cause them. This provides drug discovery scientists with the possibility to identify and develop a ‘third generation’ of drugs that now offer the exciting potential to target and modify the underlying biological processes themselves.

Our Fragile X work

FXS is a particularly good example of a condition where we have a very good understanding of the causes, such that we are in a position to now consider therapeutic approaches to addressing the underlying biology.

We know that FXS is a genetic disorder caused by a change in the fragile X (FMR1) gene. Each of our 20,000 or so genes correspond to the production of an individual protein and the FMR1 gene is associated with the production of FMRP: a protein important for many processes through the body, including the development of brain cells. The change in the FMR1 gene means that there is very little, if any, FMRP produced. This causes a challenge for researchers developing drugs for Fragile X, because drugs generally aim to alter the function of the protein involved with the condition. However, in Fragile X the protein is absent so cannot be targeted! Although the simple solution would be to somehow replace the missing FMRP by giving this protein in a pill, it is not technically possible to give an individual a protein that somehow finds its way not only into the brain but thereafter into the right parts of the nerve cell to seamlessly resume normal function.

However, the change to the single Fragile X gene and its associated protein (FMRP) has a widespread cascade of effects, some of which we can hope to target with medications. Hence, FMRP acts as a hand-brake on the production of a variety of other proteins critical to communication between brain cells at the point where they contact (synapses). So, when there is a lack of FMRP in people with FXS, the hand-brake is removed and the function of a number of other proteins is increased. In turn, this leads to abnormalities in the synapses of individuals with FXS. The LIMK1 protein is one of those proteins affected by the lack of FMRP in FXS. Specifically, recent scientific data shows that LIMK1 becomes increasingly active as the FMRP hand-brake is released and that LIMK1 is a critical regulator of other proteins that control the structure and function of synapses. Consequently, we believe that by developing drugs which reduce the increased activity of the LIMK1 protein in FXS, we will be able to reduce the changes in synaptic structure and function that underpin some of the symptoms associated with FXS.

The science is very interesting and our hypothesis is clear and we already have some chemical structures (compounds) that inhibit the activity of LIMK1. However, these compounds are weak and our project funding is intended to improve their potency and make them more “drug-like”. The process of drug development is slow, and even if we are successful, we remain at least 5 years away from having an optimised compound, (i.e. drug) ready for clinical trials. The phrase “if we are successful” is an important caveat since the drug discovery process is long, tortuous and unpredictable and many different things outside of our control can, and often do, go wrong. Nevertheless, we start this journey funded by the MRC who thankfully recognise the unmet medical need, and to whom we are extremely grateful. Moreover, armed with an enthusiasm that is tempered by pragmatism we will retain a strong focus on the patient and we are determined to try our best to make a difference to the FXS community.

Authors: Professor Simon Ward & Professor John Atack


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