PDF(Pubmed)
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 HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, 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/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 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/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 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.
摘要：
罕见的早发性下尿路疾病包括膀胱功能成熟的缺陷。目前的治疗不针对这些疾病的主要病理生物学。有些具有单基因基础，如尿面部，或者奥乔亚,综合征（UFS）。这里,膀胱不能完全排空，因为其流出道不完全松弛，随后的尿脓毒血症会导致肾衰竭。UFS与编码乙酰肝素酶-2的HPSE2的双等位基因变体相关。这种蛋白质在骨盆神经节中检测到，支配膀胱和控制排尿的自主中继站。Hpse2突变小鼠的膀胱流出道显示出受损的神经源性松弛。我们假设出生后不久的HPSE2基因转移将改善这种缺陷，并探索了一种基于腺相关病毒（AAV）载体的方法。AAV9/HPSE2，携带由CAG驱动的人类HPSE2，静脉内给予新生小鼠。在产后第三周，寻求转基因转导和表达，并进行离体肌电图检查以测量膀胱功能。在施用AAV9/HPSE2的小鼠中,在骨盆神经节中检测到病毒基因组。在处理的突变小鼠的骨盆神经节中表达人HPSE2并且变得可检测到乙酰肝素酶-2。尸检时,野生型小鼠的膀胱是空的,而在突变小鼠中膀胱均匀扩张，通过AAV9/HPSE2治疗改善的缺陷。治疗学上,AAV9/HPSE2可显着改善Hpse2突变体膀胱流出道的神经源性松弛受损。突变逼尿肌平滑肌受损的神经源性收缩力也得到了显着改善。这些结果构成了固化UFS的第一步，一种以膀胱自主神经病变为特征的临床毁灭性遗传病。
