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Central Nervous system Gene therapy to treat obesity Bardet-Biedl Syndrome (BBS). Analysis of the BBS brain development

Bardet-Biedl syndrome (BBS) is a debilitating, often life-limiting heritable multisystem disorder caused by dysfunction of non-motile cilia (ciliopathy). There is currently no cure for BBS, a disease characterised by early onset blindness, severe obesity, complex endocrine dysfunction, cognitive impairment and renal failure. Obesity, learning difficulties and behavioural deficits in BBS patients are always being linked to Central Nervous System (CNS) dysfunction.

It has been reported CNS abnormalities in brain patients and adult BBS mouse models. Those morphological defects usually consist in enlarged ventricles and reduced mass of the hippocampus and striatum. However, it is unknown the development and/or degeneration of those affected brain areas and it is also not clear how their disruption modulate the phenotype in BBS animal models. Studying the hippocampal-hypothalamic regions development in Bbs1 and Bbs5 mutant mice lines will help to understand how the BBS genes regulate these pathways.

Our group is developing gene therapy protocols in order to treat BBS patients. We are using Bbs1M390R/M390R knock-in mice as an animal model to test our viral constructs. We design Adeno-associated virus (AAV) to transduce a BBS1 human copy delivered intracranially. There are different features that can be checked on those animals to analyse the efficacy of the gene therapy; from the recovery of the retinal thickness or the recovery of the animal weight. However, we lack of a robust molecular readout to monitor if the treatment is efficient in the CNS.

The aim of this project is to find features that can be quantified to be used in the future to test the efficacy of treatments. We will analyse the differences between mutants and control brains, studying a time series including juvenile and mature brains. We will focus specially in the treatment of hippocampal and hypothalamic areas that have been shown to possibly be affected in BBS patients. Details of the project can be asked in advanced.

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

  1. Contact the supervisor by email or phone to discuss your interest and find out if you would be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
  2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
  3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

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This is a self funded topic

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.

Meet the Supervisor(s)

Victor Hernandez - Over the last ten years I have focused my career in studying of the molecular mechanisms behind human genetic disorders such as ciliopathies and craniofacial anomalies. The final aim of my research is to find a therapeutically solution for these untreatable disorders and cure or alleviate their symptoms. My interest have been focused in Bardet-Biedl Syndrome (BBS), a multi-syndromic disorder with characteristic truncal severe obesity, brain anomalies and retinal degeneration. At a molecular level, I have introduced the concept that the actin cytoskeleton is linked to cilia and play an important cellular role in ciliopathies such BBS. My research have contributed to the development of animals models to study ciliopathies including zebrafish and BBS mouse models. My work with these mouse models have been an important tool to comprehend the biological progression of the retinal degeneration and obesity. I have help to broad our understanding of the origins of the retinal and obesity phenotypes in BBS, proving how they show a great variability within the penetrance of the phenotypes which is important to understand in the scientific community want to test possible therapies on them. However, on top of all these efforts I consider that my most important contribution is the development of gene therapy solutions to treat obesity and retinal degeneration in BBS. In collaboration with many groups I have proven that the use of adeno-associated virus (AAV), as vectors to deliver corrected copies of BBS genes, are able to prevent retinal degeneration, obesity and CNS malformations in our BBS mouse models. This have led to a patent application, gene therapy for ciliopathies, which have one single aim; attract funding to start clinical trials in BBS patients. At the beginning of this journey we knew little over the function of the BBS genes, and we are now in a situation where a therapy appears as a real possibility. This is pushing me forward to improve our knowledge brain, obesity and retinal defects in ciliopathies and BBS, to test our therapies and all of this should be achieved using the best collaborative efforts and state of the art technology.