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First steps towards gene therapy for congenital bladder disease

Project Description

In the congenital disease urofacial syndrome (UFS), urinary bladder voiding is incomplete due to poor co-ordination between detrusor muscle contraction and bladder outlet relaxation. This dyssynergia leads to urosepsis and kidney failure. Previously, our research group found that UFS is caused by recessive mutations of either HPSE2, encoding a heparanase enzyme inhibitor, or LRIG2, encoding a putative modulator of receptor tyrosine kinase signalling. Our ongoing research suggests that these molecules fine tune the pattern of bladder nerves that control urinary voiding. Our Lrig2null mouse model of UFS has an abnormal urination profile. During development of the Lrig2null bladder innervation is initially normal, but becomes disorganised during postnatal maturation. We believe this peripheral neuropathy causes the bladder voiding dysfunction.

Use of viral vectors in gene therapy is a hugely exciting area of research. The adeno associated virus (AAV) alone has been used in over 170 gene therapy clinical trials, targeting diseases such haemophilia B and neurological disorders such as Alzheimer’s and Parkinson’s. Our preliminary data with AAV9 shows that intravenously administered virus can deliver a reporter gene into the pelvic ganglia of baby mice. This project will use AAV9 delivery of Hpse2 and Lrig2 into mouse pelvic ganglia cell bodies to cure mutant mice of UFS. The student will optimise AAV9 delivery of transgenes into neuronal cell bodies in pelvic ganglia, refine this protocol for transducing Hpse2 and Lrig2, and evaluate amelioration of the urinary phenotype of UFS mice that have been treated. This study will be the first to determine whether gene therapy is a possibility for a congenital bladder disease. The vectors we will study are similar to those already in use in human gene therapy trials. Therefore, the results will inform translation to clinical therapies for UFS, a rare but devastating renal tract disease.

The applicants are expected to have (or expect to obtain) an upper second class honours degree in a related subject, such as Genetics, Molecular Biology or Biochemistry. If applicants have (or expect to obtain) a research based MSc degree, a merit or distinction level is required.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor ().


Roberts NA, Woolf AS, Stuart HM, Thuret R, McKenzie EA, Newman WG, Hilton EN. Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus. Hum Mol Genet 23:4302-4314, 2014.

Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, Gülpınar O, Süer E, Yalçınkaya F, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.

Stuart HM, Roberts NA, Hilton EN, McKenzie EA, Daly SB, Hadfield KD, Rahal JS, Gardiner NJ, Tanley SW, Lewis MA, Sites E, Angle B, Alves C, Lourenço T, Rodrigues M, Calado A, Amado M, Guerreiro N,Serras I, Beetz C, Varga R-E, Silay MS, Darlow JM, Dobson MG, Barton DE, Hunziker M, Puri P, Feather SA, Goodship JA, Goodship THJ, Lambert HJ, Cordell HJ, the UK VUR Study Group, Saggar A, Kinali M, the 4C Study Group, Lorenz C, Moeller K, Schaefer F, Bayazit AK, Weber S, Newman WG, Woolf AS. Urinary tract effects of HPSE2 mutations. J Am Soc Nephrol 26:797-804, 2015

Buckinx R, Van Remoortel S, Gijsbers R, Waddington SN, Timmermans JP. Proof-of-concept: neonatal intravenous injection of adeno-associated virus vectors results in successful transduction of myenteric and submucosal neurons in the mouse small and large intestine. Neurogastroenterol Motil 28:299-305, 2016

Mattar CN, Wong AM, Hoefer K, Alonso-Ferrero ME, Buckley SM, Howe SJ, Cooper JD, Waddington SN, Chan JK, Rahim AA. Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates. FASEB J 29:3876-3888, 2015

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