
HPSE2遺伝子導入療法は、尿路性器症候群マウスモデルの膀胱機能障害を改善する。


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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.

Summary In the first gene therapy for genetic bladder disease, we cured autonomic neurons using AAV-mediated gene delivery in a mouse model of urofacial syndrome.

### Competing Interest Statement

The authors have declared no competing interest.

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

遺伝性膀胱機能障害に対するヒト-hpse2-遺伝子導入療法の有効性


遺伝性膀胱機能障害に対するヒト HPSE2 遺伝子導入療法の有効性


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慢性ストレスによりNAC由来のmiR-335-3pが減少し、Fosの発現が増加することで、NFATC1シグナル経路が活性化され、オステオクラストの分化と機能が亢進し、最終的に骨粗鬆症を引き起こす。


It has been well-validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress-induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly down-regulated in the nucleus ambiguous (NAC), serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in Fos. Further studies demonstrated Fos was upregulated in CUMS osteoclast, and the inhibition of Fos suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, Mmp9, in miR-335-3p restrained osteoclasts. In conclusion, this work indicated that psychological stress may down-regulate the miR-335-3p expression, which resulted in the accumulation of Fos and the up-regulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.

Impact statement miR-335-3p, which targets FOS and inhibits its activation of NFATC1 signaling, is an important regulator for osteoclast function and responsible for the psychological stress induced osteoporosis

### Competing Interest Statement

The authors have declared no competing interest.

Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast

慢性ストレスが-mir-335-3p-fos-シグナリングを介してオステオクラストの骨代謝を乱す


慢性ストレスが miR-335-3p/Fos シグナリングを介してオステオクラストの骨代謝を乱す
