Inhibiting neutral amino acid transport for the treatment of phenylketonuria

• DOI: 10.1172/jci.insight.121762
• Publication Date: 2018-07-25T15:01:04Z
• Authors: Adam M. Belanger; Malgorzata Przyby...; Estelle Gefteas; Matthew Furgerson; Sarah Geller; Alla Kloss; Seng H. Cheng; Yunxiang Zhu; Nelson S. Yew
• Keywords: Phenylalanine hydroxylase; Phenylketonurias

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