Imperial College London

Tuesday 18 November 2003
DJ Jono Coleman presents genetic research grant to Imperial College Scientists

Jono Coleman, breakfast DJ on London’s Heart 106.2 radio station will today meet scientists at Imperial College London who are tackling a rare genetic disease thanks to funds from the charity the Lowe Syndrome Trust.

Mr Coleman, Patron of the Charity, will hand over a cheque for £49,785 to Dr Ramon Vilar-Compte and Dr. Rudiger Woscholski, which will fund three years of research at Imperial into Lowe Syndrome. DJ Jono Coleman with Marianna Mirabelli, a PhD student in the Vilar-Compte lab

Lowe Syndrome is a genetic disorder that affects only boys and produces bilateral cataracts, muscle weakness, kidney and brain development problems. It is a rare X chromosome-linked disease, thought to affect up to 10 per million male births.

The disease was first recognised in 1952 by Dr Charles Lowe, and is caused by a gene (Ocr1) mutation which makes a defective version of an enzyme named OCRL.

The money will support research into a chemical test for signs of the Lowe enzyme, hopefully leading to a fast, user-friendly and reliable method to help doctors diagnose and treat the Syndrome. Currently only expensive and unreliable DNA testing is available in the UK for Lowe Syndrome.

The Lowe Syndrome Trust was set up by Lorraine Thomas, mother of ten-year old son Oscar who has the disease, in 2000. Her son was eventually diagnosed with the incurable syndrome in 1999.

Mrs Thomas, chair of the Trust says: “We were devastated when Oscar was diagnosed with the syndrome at the age of  nearly 6.  All of the chidren are partially sighted or blind due to cataracts and some never ever walk.  Even Lowe children (boys only) who are doing quite well with the disease, sadly deteriorate with the condition and most die in their teens.  I am so grateful for the research being carried out Imperial College which will  hopefully  produce a simple test for Lowe syndrome leading to the development of medicines to better regulate the metabolic imbalance or perhaps even lead the way of synthesizing the missing enzyme.  The aim of the Trust is to raise awareness and funding for research projects such as the one we are funding today”.   Mr Coleman said “Having met Oscar, I am delighted to be able to help these little boys who have big personalities”.

The Trust’s money will be used to fund PhD student, Marianna Mirabelli, who recently completed a Masters degree in Biomolecular Sciences at the College.

The defective OCRL enzyme in Lowe Syndrome means that carriers can not control levels of a molecule named PIP2, which in turns leads to development of the symptoms of Lowe Syndrome.

Jono, Trustee Carolyn Mitchell, Dr Rudiger Wolzcholski, Trustee Lorraine Thomas, Dr Ramon Vilar Compte & Marianna Mirabelli,PIP2 belongs to an important group of signalling molecules named inositol lipid phosphates, which are involved in pathways that malfunction in a number of other diseases, including some cancers, neurodegenerative disorders and heart disease.

Together with supervisors Dr Vilar-Compte and Dr Rudiger Woscholski, Miss Mirabelli will help to engineer a synthetic receptor to which only their target, PIP2, will be able to bind.

Chemist Dr Vilar-Compte will use his expertise in building receptor molecules to order – combining fields known as supra-molecular chemistry and molecular recognition – to make a receptor that will fit the PIP2 molecule like a lock built for a key.

“Our ‘lock’ must not be so strong or sticky that it never lets go of the key, nor too easy or loose for anything other than the key with exactly the right arrangement to fit,” says Dr Vilar-Compte.

“However, we are not fishing in the dark. There is no reason not to think we can do it. We already know certain parts of the puzzle and a number of the building blocks are ready,” he adds.

Working alongside Ramon, biologist and cell signalling expert Dr Rudiger Woscholski is confident that they will succeed in building the Lowe Syndrome test, helping the Trust towards realising its long-term vision Dr Woscholski describes the task confronting them as like making a bespoke glove to fit a hand: “Each finger needs a different fit, it has a different length or diameter. At the moment we have a number of individual fingers, but the challenge is to make the full hand glove.”

“The focus of our work, this diagnostic tool will not only greatly improve matters for Lowe patients in terms of diagnosis, but it will also significantly help other scientists. The test will contribute to the long-term vision shared by us at Imperial and the Lowe Syndrome Trust of making a drug, a small synthetic molecule, that will chew and cut the PIP2 molecule, just like the thing that Oscar Thomas is missing,” says Dr Woscholski. Dr Vilar Compte is a Senior Lecturer in the Department of Chemistry and Dr Rudiger Woscholski is Lecturer in the Department of Biological Sciences at Imperial.

Photographs of the visit and Jono Coleman handing over the cheque to the scientists will be available from Tom Miller on 020 7594 6704 or from Tuesday afternoon.

For more information, interviews or photographs please contact: Tom Miller, Imperial College London Press Office Tel: +44 (0)20 7594 6704 Mob: +44 (0)7803 886248 Email:

Notes to Editors About Lowe Syndrome Lowe Syndrome is a degenerative gene disorder that can occur with no family history, affecting boys with multiple physical and mental handicaps including cataracts in both eyes, muscle weakness (hypotomia – floppy baby syndrome), kidney problems including kidney stones and loss of essential nutrients, brittle bones, arthritis, poor growth, mental impairment (autistic spectrum disorder) and epilepsy. The Syndrome has a wide variation with some children mildly affected while others are blind, unable to walk and with severe mental impairment.

About the Lowe Syndrome Trust The Lowe Syndrome Trust is a UK Charity formed in June 2000 as an affiliate of the USA Lowe Syndrome Association (LSA). As most children’s charities exclude funding medical research, the primary aim of the Trust is to encourage medical research into Lowe Syndrome and provide UK support by raising funds for research into Lowe Syndrome in the UK, and internationally through the LSA and worldwide affiliates. The charity is funded by voluntary donations and is also supporting research at Great Ormond Street Hospital, Dundee University Biocenter, University College London and USA.

Web site:   Grampian TV news clip on Dundee award About Imperial College London Consistently rated in the top three UK university institutions, Imperial College London is a world leading science-based university whose reputation for excellence in teaching and research attracts students (10,000) and staff (5,000) of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and management and delivers practical solutions that enhance the quality of life and the environment – underpinned by a dynamic enterprise culture. Website: Progress Reports   June05report  Summary

Lowe syndrome is a rare disease that is affecting mostly the eye, brain and kidneys, which is why this disease is also known as ³oculocerebrorenal syndrome of Lowe² (OCRL). These symptoms are caused by the loss of functionality of a single gene product, the OCRL phosphatase. This phosphatase is an enzyme that regulates the cellular levels of an important inositol lipid, phosphatidylinositol 4,5-bisphosphate (PIP2). Consequently, high levels of PIP2 are an indication of the disease, which together with reduced phosphatase levels form the basis for the currently employed biochemical diagnosis of OCRL. However, the biochemical OCRL diagnosis is currently based on a cumbersome, laborious and expensive detection method, which is not routinely available. This is hindering any progress in the diagnosis of this already difficult to diagnose disease. A better and easier detection method for cellular PIP2 levels would therefore provide the NHS with a suitable tool to diagnose this disease at the earliest possible stage, and consequently foster the necessary, but so far missing, development of clinical research into this area.

The Lowe Trust funded 2 years ago our research on a new diagnostic method for detecting PIP2 levels in biopsy samples. This will be achieved by generating a chemical compound that is capable of binding PIP2. This PIP2 receptor would be coupled to a dye, which facilitates the sensing of the bound PIP2 by the chemical receptor. The synthesis of this receptor is based on a modular approach, which will combine several chemical modules recognising phosphates and alcohol functionalities on the inositol headgroup present on the PIP2. This approach gives us the flexibility to screen for high binding affinities and thus high specificity. The assembly of the modules by chemical linkers of various length and flexibilities to generate the best receptors for PIP2 detection is currently being carried out. These chemical receptors will then be tested in the final year of the funded research programme for specificity and suitability. The last year of the funded research project was designed to get this prototype receptor synthesized and thus generate a ³proof-of concept², which is now likely to be achieved. However, while the generated prototypes will be characterised in sufficient detail at the end of this project, we will have neither the resources nor time to test the diagnostic capabilities on biological samples.

2006 Progress Report Summary:  The project has progressed well and most of the aims initially stated have been investigated (although not fully achieved yet). There has been some delay in achieving the milestones stated in the initial proposal, particularly in the parallel synthetic approach and parallel evaluation of the receptors prepared (milestones M3 and M6 for the parallel synthetic approach and M5 for the incorporation of the luminophore on the receptors). This has been due to two main factors:a) Six months after this project had started, the PI of the project (R. Vilar) moved to a new institution (the Institute of Chemical Research of Catalonia). Although the student involved in the project (Marianna Mirabelli) did not stop her research work during this move, there was obviously a small delay of approximately 2 months.b) The optimization of the parallel synthetic approach took a longer time than initially expected. As described above, part of the problem comes form the bifunctional nature of the building blocks employed which lead to the formation of unwanted by-products. Although the steps employed in the synthetic methodology are all well documented, the formation of asymmetric molecules with a relatively high number of functionalities is not straight forward. Consequently, more time was devoted to optimizing each of the steps. Currently, the problems initially encountered have been solved and it is hence expected that a large number of potential receptors will be prepared soon.Related outputs and “cross-fertilization”To date, we have not yet published any of the results coming out directly from this project (although one publication is currently in preparation and it is expected that a second one will follow). However, it should be pointed out that there have been related publications and grants from the principal investigator’s laboratory that will have a direct effect on this project During the two years the principal investigator (R. Vilar) spent in the Institute of Chemical Research of Catalonia (ICIQ) his laboratory received extra funding to carry out research on “Metalla-receptors for phosphorylated species” from the Ministry of Science of Spain (105,800 euros). One of the aims of this project is to develop metal-containing receptors for the recognition of di- and tri-phosphorylated species – such as the substrates being targeted in the OCRL project. Hence, it is expected that interaction between the researchers involved in the two projects will provide an advantage for the development of the receptors.Besides the extra funding already obtained, the principal investigator’s laboratory has recently published some papers on the general area of molecular recognition of anionic species (with an impact on the development IP3/PIP2 receptors) which are worth pointing out:a) J.A. Tovilla, R. Vilar, A.J.P. White, “A di-palladium urea complex as molecular receptor for anions”, Chem. Comm., 2005, 4839.b) P. Diaz, D.M.P. Mingos, R. Vilar, A.J.P. White, D.J. Williams, “Anion templated synthesis of metalla-cages as means for the colorimetric detection of chlorides”, Inorg. Chem. 2004, 43, 7597.

Dr. Ramon Vilar
Department of Chemistry
Imperial College London
South Kensington
London SW7 2AZ
United Kingdom

Telephone: +44 (0)20 7594 1967


The chemical synthesis of chemical receptors for the metabolites of OCRL will enable the design of diagnostic tool to test the occurrence of Lowe syndrome in patients much more cost effective and much easier. The extension towards the currently funded research will build on the achievements of the chemical synthesis and will be used for the necessary biological testing of the diagnostic application of these compounds. In the long term further funding will be needed to optimize the current chemical receptors using the input from the biological testing. This could involve changing the recognition modules towards particular chemical functional groupings such as hydroxyls or phosphates or the re-arranging of the spacing between these modules. The optimized compounds will go a similar routine of biological testing, which will hopefully result an several lead compounds for the diagnostic test kit. However, at the same time the compounds  can be screened for their effectiveness to scavenge the cellular PIP2, which are elevated in Lowe syndrome. This will be tested in suitable cell lines mainly by microinjection to avoid any cell delivery problems. Alternatively, in vitro methods such binding assays can be used to get a handle on lipid specificity and affinity.  Overall the second phase will involve further chemistry synthesis to improve the current compound towards better selectivity and affinity as well as cellular applicability. Layman’s Summary 2006.

The Lowe Trust funded a PhD project on the development of a chemical receptor for the lipid substrate (PIP2) of the OCRL enzyme, deletion of which is causing the Lowe syndrome. Chemical receptors are small molecules that can bind to other molecules in a specific fashion. The receptor designed and tested in the Lowe trust funded PHD project aimed to recognise the vicinal phosphate and alcohol groups on the inositol headgroup of the lipid substrate. In order to develop such a chemical receptor, it is necessary to first prepare a series of building blocks that can selectively interact with specific parts of the targeted molecule (i.e. the phosphates or the head group). These building blocks can then be assembled together (using a modular approach – like a chemical ³Lego²) into a series of potential receptors, generating a small library of compound that can be evaluated and screened for their ability to interact with the targeted molecule. In parallel, a way of visualising this interaction needs to be devised. This can be based in optical changes such as a change of colour or luminescence of the receptor when it binds to IP3 or PIP2.

Over the past three years, we have managed to tackle most of these challenges establishing the proof-of-concept. More specifically, we have:

  • Developed a library of molecular building blocks with good binding capabilities to different parts of the targeted IP3/PIP2
  • Assembled these building blocks in different combinations to achieve a small library of receptors
  • Evaluated the binding abilities of these receptors towards IP3 in aqueous solutions
  • Demonstrated that some of these receptors can indeed bind IP3 selectively, in aqueous solution and this molecular event can be detected by a colour change

It is worth noting two key achievements of the research carried out over the past three years: the receptors are able to bind with good affinity the targeted molecule in aqueous solutions and they do this with a good degree of selectivity (i.e. they bind IP3 better than other competing analytes in the medium).

Where are the challenges for the future? Although the past three years have been successful, we recognise that there are still several important challenges that need to be tackled. Some of them are:

  • Increase the binding affinity of the receptors – for these receptors to be successfully used as part of a diagnostic tool (and eventually as a component of an artificial enzyme²) their binding affinities need to increase a couple of orders of magnitude. We propose to do this by including metal complexes as modules for the synthesis of a second generation of receptors.
  • Improve selectivity – although the receptors can discriminate well between different competing species, we need even better selectivity (this will be directly linked to the above)
  • Better means of detecting the ³binding² event – so far, the change in colour observed when the receptor interacts with IP3 has been based in the so-called displacement assay of a dye from the receptor. Now we want to take one step forward an incorporate the optical reporter as one of the building blocks of the receptor.

All these improvements will strengthen the current lead compound towards a real chemical alternative to investigate OCRL dependent signalling and may even be the foundations of a future drug development programme to tackle the symptoms of Lowe Syndrome.