Evaluating genetic therapeutics in ciliopathies

Lead Research Organisation: University College London
Department Name: Institute of Child Health


Bardet-Biedl Syndrome (BBS) is one of the most common and well described 'ciliopathies'. This rapidly expanding group of conditions is characterised by defects in cell surface projections known as cilia which play a vital role in cell to cell communication. BBS affects more than 400 people in the UK. It is characterised by loss of vision, obesity, learning difficulties, kidney dysfunction, extra fingers and toes, and poorly developed genitalia.

Visual loss typically occurs in late childhood. It is a consistent and particularly devastating consequence for most patients with this disease, closely followed by exponential weight gain, which proves extremely difficult to control, and predisposes disproportionately to many lifestyle diseases, such as high cholesterol and blood pressure. No effective treatment exists for BBS. Patients are treated symptomatically with limited effect, and currently no treatment prevents or slows the devastating visual loss.

A research group at the Institute of Child Health with a special interest in ciliopathies is in pursuit of innovative treatments for this debilitating condition. The team is developing two new 'personalised genetic drugs' with a view to curing or slowing the progression of visual loss and hopefully treating some of the other features of BBS. 'Personalised genetic therapeutics' refers to treatments that are targeted specifically to the defects in a patient's genetic make-up that have caused their condition.

One of these treatments, Ataluren, has been trialed in patients with other genetic disorders with promising results. Genes encode proteins which determine how our bodies grow and develop. Ataluren works by a tricking the cellular mechanism that 'reads' our genetic code (DNA) in the process of producing proteins. Fourteen per cent of people with BBS have 'premature stop' sequences in genes associated with this disorder. This means that in addition to the appropriate 'stop' signals in that gene, the disease causing genetic alteration has produced a new 'stop' signal producing a shortened, defective version of the protein. Ataluren targets the disease-causing 'stop' signal and is able to 'read through' without stopping and producing a near normal protein.

Ataluren has been used previously in humans and is known to be safe with limited side effects. The next step is to prove that it has the required effect on vision and obesity before it can be introduced into a clinical trial. The aim is to deliver this exciting new treatment option to patients within the next two years.

An estimated 9% of people with BBS in the UK have a disease-causing genetic change that leads to the the remaining genetic sequence in that gene being misinterpreted. A novel treatment, known as 'exon skipping therapy', works by allowing the gene reading mechanism to 'skip' the segment of genetic material that contains the disease causing gene change. Trials on other genetic conditions have shown that this type of treatment has a proven clinical effect and that a near normal protein can be produced. Each 'exon skipping therapy' is highly specific to a particular gene change and therefore each of these treatments is a novel drug. A new drug must first be designed and tested to assess the side effect profile and clinical efficacy before it can safely be introduced into a clinical trial. We aim to do this in the next three years.

Developing these new drugs is an exciting prospect not only for patients affected with BBS but also for people affected with other 'ciliopathy' disorders. BBS is an attractive candidate disease for this kind of treatment as it offers measurable short and long term outcomes since weight loss and visual decline can be objectively charted. Once proof of principle has been established in this condition therapeutic design and trials can be extended to other genetic conditions within the ciliopathy spectrum and beyond.

Technical Summary

Investigate novel therapeutic approaches in Bardet-Biedl Syndrome (BBS) using genetic therapeutic agents which have demonstrated proof of principle in other recessive conditions: antioligonucleotide (AON) therapy and read-through therapy.

1. Show that targeted AON therapy could be developed to have a measurable therapeutic effect on BBS patients with frameshift/splice site mutations (n=27, 9% of the BBS patient population).
2. Investigate the efficacy and clinical application of read through therapy on BBS patients with paired nonsense mutations (n=43, 14% of the BBS patient population).

An AON with high exon skipping potential would be designed. To determine whether the AON has exon-skipping potential in vitro I would culture immortalised fibroblasts from unrelated BBS patients as well as controls in the absence and presence of the AON. Once the specificity has been established the most effective treatment dose must be determined. Subsequent investigations will determine the phenotypic effect, efficacy and side effect profile as well as the suitability of this drug for a clinical trial.

Read-through therapy has already proven to deliver very robust results in renal cells transfected with a number of common mutations from a variety of ciliopathies. The aim is to reproduce these findings in other cell types such as the eye. Providing this delivers the expected results, I would investigate the effect of this drug on measurable outcomes including visual deterioration and body mass index. An application will be made for ethical approval to introduce Ataluren into a clinical trial.

We have access to a large patient population (>400) through the nationally commissioned BBS clinic, and close ties with a very proactive patient support. If these therapeutic strategies deliver the expected results we will implement them into clinical practice and develop them further for use in other ciliopathies.

Planned Impact

Personalised genetic medicine is currently at an early stage of development and developing therapeutic strategies will not only benefit patients with Bardet-Biedl Syndrome (BBS). BBS offers an excellent model for research as the clinical manifestations of the condition deliver objective, measurable outcomes such as visual function and body mass index. Successful development and implementation of personalised genetic medicine for BBS will pave the way for the development of personalised therapeutics in other ciliopathies and monogenic diseases in general.

Identifying and developing an effective treatment strategy in collaboration with the pharmaceutical industry would have remarkable benefits for patients with BBS. Visual deterioration in these patients constitutes the main clinical and social burden for patients with BBS. It affects patients' confidence and quality of life as well the ability to enter the job market and exercise to maintain a healthy weight. As a result of blindness many patients are reliant on social welfare to provide a safe living and working environment for the duration of their life. If the visual deterioration is abrogated through therapeutic intervention this could have significant implications for the patients' quality of life and reliance on social welfare.

The potential impact on the National Health Service is significant. BBS affects more than 400 patients in the UK and the prevalence of monogenic disorders is estimated at 1 in 100 live births. Trailblazers in the field have already demonstrated proof of principle for genetic therapeutics in other conditions such as Duchenne Muscular Dystrophy.

We aim to deliver read through therapy and antisense oligonucleotide therapy into a clinical trials patients with BBS within the next five to ten years. Provided the treatment delivers the expected results we will implement it into the medical management of BBS patients and develop it further for patients with other ciliopathies.

This fellowship would offer unique training and research opportunities and will provide an excellent basis for developing a career in medical academic research. It will develop my skills both in the laboratory and clinic and provide a broad training in experimental design, cell culture, animal work, and statistical analysis. I will gain an understanding of personalised genetic medicine and therapeutic drug development.

This project offers the opportunity to develop mutually collaborative work with other researchers in personalised genetic therapeutics both within the Institute of Child Health, nationally and internationally, in a joint effort to bring these exciting developments into clinical practice.


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Forsythe E (2018) Managing Bardet-Biedl Syndrome-Now and in the Future. in Frontiers in pediatrics

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Forsythe E (2017) Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome. in Journal of the American Society of Nephrology : JASN

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Kenny J (2017) Toward personalized medicine in Bardet-Biedl syndrome. in Personalized medicine

Title Max Perutz public engagement prize -shortlisted 
Description Max Perutz public engagement prize -shortlisted 2014. 
Type Of Art Creative Writing 
Year Produced 2014 
Impact Shortlisted for the Max Perutz Public engagement prize. Subsequently invited to publish on the on the UCL blog 'Me and My Genes'. 
URL http://blogs.ucl.ac.uk/clinical-molecular-genetics/
Description Board member of the Ciliopathy alliance
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Title Developing protocol for growing urine derived renal epithelial cells 
Description Developing protocol for growing urine derived renal epithelial cells 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact This has been developed further and is in the process of being used by industry for drug library screening purposes. 
Title IPSC differentiation 
Description With collaborators we have been modifying methods for iPS cell differentiation in to retinal and kidney tissues. 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact This could have a significant impact on our ability to design new drug screening strategies 
Title BBS databases 
Description Bardet-Biedl Syndrome DNA and cell repository bank held at ICH. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact I am using this repository to assess the effect of my genetic drug therapies. 
Title BBS fibroblasts library 
Description BBS fibroblasts library 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? No  
Impact Being used for development/ testing of new drugs for ciliopathies 
Title Clinical pilot trial 
Description Pilot trial assessing the effect of exercise on hippocampal structure and function in patients with Bardet-Biedl syndrome. Successful outcome with increased hippocampal volume and improved memory scores. 
Type Therapeutic Intervention - Physical
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Increased memory, improved confidence in physical skills and improved mood in patients who took part in the intervention. 
Description 3 Minute Thesis competition 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 3 Minute thesis competition across universities. I won the competition for the UCL Great Ormond Street Institute of Child Health. I will go on to represent the ICH at the UCL competition in April. Marked by external examiners. Presented to faculty and students at the ICH.
Year(s) Of Engagement Activity 2018
Description Engagement with BBS UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBS UK patient support society. I co-chaired the annual patient conference whereby the latest advances in medical research are reported. I also run annual workshops for the patients on a variety of issues relating to Bardet-Biedl syndrome.

As above
Year(s) Of Engagement Activity 2014,2015,2016
URL http://www.lmbbs.org.uk/