HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants ofHPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts ofHpse2mutant mice display impaired neurogenic relaxation. We hypothesized thatHPSE2gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach.AAV9/HPSE2,carrying humanHPSE2driven byCAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, andex vivomyography was undertaken to measure bladder function. In mice administeredAAV9/HPSE2, the viral genome was detected in pelvic ganglia. HumanHPSE2was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated byAAV9/HPSE2treatment. Therapeutically,AAV9/HPSE2significantly ameliorated impaired neurogenic relaxation ofHpse2mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.