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Purine nucleoside phosphorylase as a target to treat age-associated lower urinary tract dysfunction

Abstract

The lower urinary tract (LUT), including the bladder, urethra and external striated muscle, becomes dysfunctional with age; consequently, many older individuals suffer from lower urinary tract disorders (LUTDs). By compromising urine storage and voiding, LUTDs degrade quality of life for millions of individuals worldwide. Treatments for LUTDs have been disappointing, frustrating both patients and their physicians; however, emerging evidence suggests that partial inhibition of the enzyme purine nucleoside phosphorylase (PNPase) with 8-aminoguanine (an endogenous PNPase inhibitor that moderately reduces PNPase activity) reverses age-associated defects in the LUT and restores the LUT to that of a younger state. Thus, 8-aminoguanine improves LUT biochemistry, structure and function by rebalancing the LUT purine metabolome, making 8-aminoguanine a novel potential treatment for LUTDs.

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Fig. 1: Inhibition of PNPase with 8-aminoguanine ‘rebalances’ the purine metabolome and thereby restores ageing-associated abnormalities in LUT form and function.
Fig. 2: Ageing increases collagen fibre stiffness but this can be restored to a younger state with 8-aminoguanine treatment.

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The authors contributed equally to discussion of the content, writing, reviewing and/or editing of the manuscript before submission.

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Correspondence to Lori A. Birder.

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Both authors are co-inventors on a (pending) patent, PCT/US2020/022697, which relates to the field of purine nucleoside phosphorylase (PNPase) inhibitors and PNPase purine nucleoside substrates for treating bladder and urethra dysfunction or disease.

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Birder, L.A., Jackson, E.K. Purine nucleoside phosphorylase as a target to treat age-associated lower urinary tract dysfunction. Nat Rev Urol 19, 681–687 (2022). https://doi.org/10.1038/s41585-022-00642-w

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