Human <i>HPSE2</i> gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome.

Abstract

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 of <i>HPSE2</i>, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of <i>Hpse2</i> mutant mice display impaired neurogenic relaxation. We hypothesized that <i>HPSE2</i> gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (<i>AAV</i>) vector-based approach. AAV9<i>/HPSE2,</i> carrying human <i>HPSE2</i> driven by <i>CAG</i>, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9<i>/HPSE2</i>, the viral genome was detected in pelvic ganglia. Human <i>HPSE2</i> was 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 by AAV9<i>/HPSE2</i> treatment. Therapeutically, AAV9<i>/HPSE2</i> significantly ameliorated impaired neurogenic relaxation of <i>Hpse2</i> mutant 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.