Prof K Martin, Prof J Fawcett
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
This is a project which will examine the ability of the BDNF/TrkB gene therapy to protect retinal structures in various transgenic mouse models of rare orphan diseases. The student will learn how to administer small volumes of gene therapy to the eye using intravitreal and subretinal injection techniques and to examine for efficient and long-term transgene expression in target retinal cells using immunohistochemical techniques. In some circumstances retinal cells do not normally degenerate in some of the transgenic mouse models maintained in standard laboratory housing (for example shaker-1 and abca-4 knockout mice models of Usher-1B syndrome and Stargardt disease, respectively) unlike in humans. However, human-like pathophysiology and retinal cell death can be induced when exposing animals to normal (bright) light. The student will learn to work with and improve animal models of rare inherited eye conditions so that the pathophysiology more closely resembles the human ophthalmic condition. Retinal structure and visual function will be assessed using confocal microscopy and electrophysiological techniques. A number of mouse transgenic models are currently commercially available and so the student has a high probability of generating exciting data which may indicate that the gene therapy be considered for clinical testing in a broader range of eye diseases than is currently planned.
References
Background: There are a number of rare inherited eye conditions which result from mutations within single genes responsible for normal cell metabolism and signalling that cause sight deterioration and blindness over time. Due to the limited numbers of subjects with these conditions, classical small medicinal molecule and recombinant protein drug discovery efforts to treat the small populations would not be economically viable for industrial research. However, gene therapies which can introduce gene sequences which code for the ‘normal’ functional proteins offer an exciting and promising approach to treating these conditions. However, for each rare condition, a specific gene therapy product would need to be designed, manufactured and tested in animal models and small clinical trials. Whilst this may be a viable approach for some conditions in which the orphan disease is more commonly encountered, for extremely rare mutations resulting in progressive blindness, even small scale targeted gene therapies would not be viable. For example, there have been shown to be around 50 genetic mutations responsible for a retinitis pigmentosa which results in initial poor night vision which may gradually progresses to complete loss in vision over time. Moreover, some of the mutations which result in the eye conditions are found in very large genes which would be technically very challenging to accommodate in a viral vector gene therapy product capable of targeting particular retinal target cell types. What is needed is a ‘ubiquitous’ retinal cell neuroprotective gene therapy which is capable of preventing retinal cell degeneration caused by a variety of genetic metabolic and signalling defects. We, together with the biotechnology company Quethera, have recently designed a novel gene therapy which can boost activity through the neuroprotective brain-derived neurotrophic factor (BDNF)/TrkB receptor pathway. This gene therapy is currently being progressed into clinical trials for the treatment of progressive glaucoma as it has been shown to be highly effective in preventing retinal ganglion cell death following a variety of pathophysiological insults. Due to the ability of the BDNF/TrkB gene therapy to up-regulate the generic anti-apoptotic cell survival pathway, this novel therapy may have utility in preventing other retinal cells from damage caused by different mutations.
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