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Inhibiting neutral amino acid transport for the treatment of phenylketonuria
Adam M. Belanger, … , Yunxiang Zhu, Nelson S. Yew
Adam M. Belanger, … , Yunxiang Zhu, Nelson S. Yew
Published July 26, 2018
Citation Information: JCI Insight. 2018;3(14):e121762. https://doi.org/10.1172/jci.insight.121762.
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Research Article Metabolism Therapeutics

Inhibiting neutral amino acid transport for the treatment of phenylketonuria

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Abstract

The neuropathological effects of phenylketonuria (PKU) stem from the inability of the body to metabolize excess phenylalanine (Phe), resulting in accumulation of Phe in the blood and brain. Since the kidney normally reabsorbs circulating amino acids with high efficiency, we hypothesized that preventing the renal uptake of Phe might provide a disposal pathway that could lower systemic Phe levels. SLC6A19 is a neutral amino acid transporter responsible for absorption of the majority of free Phe in the small intestine and reuptake of Phe by renal proximal tubule cells. Transgenic KO mice lacking SLC6A19 have elevated levels of Phe and other amino acids in their urine but are otherwise healthy. Here, we crossed the Pahenu2 mouse model of PKU with the Slc6a19-KO mouse. These mutant/KO mice exhibited abundant excretion of Phe in the urine and an approximately 70% decrease in plasma Phe levels. Importantly, brain Phe levels were decreased by 50%, and the levels of key neurotransmitters were increased in the mutant/KO mice. In addition, a deficit in spatial working memory and markers of neuropathology were corrected. Finally, treatment of Pahenu2 mice with Slc6a19 antisense oligonucleotides lowered Phe levels. The results suggest that inhibition of SLC6A19 may represent a novel approach for the treatment of PKU and related aminoacidopathies.

Authors

Adam M. Belanger, Malgorzata Przybylska, Estelle Gefteas, Matthew Furgerson, Sarah Geller, Alla Kloss, Seng H. Cheng, Yunxiang Zhu, Nelson S. Yew

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Figure 7

Oligonucleotide-mediated inhibition of SLC6A19 in Pahenu2 mice.

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Oligonucleotide-mediated inhibition of SLC6A19 in Pahenu2 mice.
(A) Knoc...
(A) Knockdown of SLC6A19 RNA and protein in the kidneys of PPMO-treated mice. Animals were injected intravenously (7.5 mg/kg) with Slc6a19 PPMO (19e6ei-J), control PPMO (Scrmbl-J), or saline on days 0, 1, 8, 15, and 22. Kidneys were harvested on day 25. SLC6A19 mRNA levels were measured by quantitative RT-PCR. (B) SLC6A19 protein levels in the kidney were visualized by Western blotting. (C) Immunohistochemical staining of kidney sections using an anti-SLC6A19 antibody. Slides were counterstained with hematoxylin and eosin. Original magnification, ×400. Scale bar: 100 μm. n = 10 animals/PPMO-treated groups; n = 8 animals/saline-treated group, saline; n = 4 animals/naive wild-type group. Mean ± SEM is shown

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