Abstract
Human urinary tract malformations can cause dysfunctional voiding, urosepsis and kidney failure. Other affected individuals, with severe phenotypes on fetal ultrasound screening, undergo elective termination. Currently, there exist no specific treatments that target the primary biological disease mechanisms that generate these urinary tract malformations. Historically, the pathogenesis of human urinary tract malformations has been obscure. It is now established that some such individuals have defined monogenic causes for their disease. In health, the implicated genes are expressed in either differentiating urinary tract smooth muscle cells, urothelial cells or peripheral nerve cells supplying the bladder. The phenotypes arising from mutations of these genes include megabladder, congenital functional bladder outflow obstruction, and vesicoureteric reflux. We contend that these genetic and molecular insights can now inform the design of novel therapies involving viral vector-mediated gene transfer. Indeed, this technology is being used to treat individuals with early onset monogenic disease outside the urinary tract, such as spinal muscular atrophy. Moreover, it has been contended that human fetal gene therapy, which may be necessary to ameliorate developmental defects, could become a reality in the coming decades. We suggest that viral vector-mediated gene therapies should first be tested in existing mouse models with similar monogenic and anatomical aberrations as found in people with urinary tract malformations. Indeed, gene transfer protocols have been successfully pioneered in newborn and fetal mice to treat non-urinary tract diseases. If similar strategies were successful in animals with urinary tract malformations, this would pave the way for personalized and potentially curative treatments for people with urinary tract malformations.
Highlights
This review considers prospects for biological treatments for urinary tract malformations, focusing on viral vector-mediated gene therapy
We cover several themes, including: the clinical impact and genetic bases of human urinary tract malformations; how viral vectormediated gene therapy is moving to the clinic for non-urinary tract diseases; whether fetal viral vector-mediated gene therapy might be possible; why mice are an appropriate species with which to model human genetic urinary tract diseases; technologies for viral vectormediated gene transfer in neonatal and fetal mutant mice; and some challenges to applying this technology to treat people with genetically defined urinary tract malformations
It is becoming clear that certain human urinary tract malformations are caused by mutations of genes expressed during the normal differentiation of either urothelia, or smooth muscle cells, or innervation of the urinary tract [10]
Summary
This review considers prospects for biological treatments for urinary tract malformations, focusing on viral vector-mediated gene therapy. It is becoming clear that certain human urinary tract malformations are caused by mutations of genes expressed during the normal differentiation of either urothelia, or smooth muscle cells, or innervation of the urinary tract [10].
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