Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy.

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.