Inhibiting neutral amino acid transport for the treatment of phenylketonuria.
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.
['Belanger|Adam M|AM|', 'Przybylska|Malgorzata|M|', 'Gefteas|Estelle|E|', 'Furgerson|Matthew|M|', 'Geller|Sarah|S|', 'Kloss|Alla|A|', 'Cheng|Seng H|SH|', 'Zhu|Yunxiang|Y|', 'Yew|Nelson S|NS|']
D000588:Amines D026921:Amino Acid Transport Systems, Neutral D021542:Amino Acids, Neutral D000818:Animals D001253:Astrocytes D001692:Biological Transport D001921:Brain D004195:Disease Models, Animal D005260:Female D005786:Gene Expression Regulation D030342:Genetic Diseases, Inborn D007687:Kidney Tubules, Proximal D008297:Male D008570:Memory, Short-Term D051379:Mice D018345:Mice, Knockout D060172:Morpholinos D009841:Oligonucleotides D010649:Phenylalanine D010661:Phenylketonurias D065608:Renal Reabsorption
Metabolism Amino acid metabolism Genetic diseases Therapeutics