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Non-Physiological Amino Acid (NPAA) Therapy in Pah enu2 Mice Relevance to PKU Therapy

This study focuses on selectively lowering brain phenylalanine using NPAA therapy targeting L and A systems for cognitive improvements in Pahenu2 mice. The research explores amino acid transporters and metabolic roles of LNAA, providing proof-of-principle for Phe reduction and potential combinatorial approaches. Future studies aim to optimize NPAA concentrations and assess behavior during NPAA intervention.

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Non-Physiological Amino Acid (NPAA) Therapy in Pah enu2 Mice Relevance to PKU Therapy

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  1. Non-Physiological Amino Acid (NPAA) Therapy in Pahenu2 MiceRelevance to PKU Therapy Mike Gibson, Professor and Head Section of Clinical Pharmacology Washington State University (WSU) Spokane College of Pharmacy, Spokane WA Disclosures: None

  2. Rationale and Goals • To Selectively Lower Brain Phenylalanine • NPAAs targeting L and A systems (BBB and gut) • Maintain Other LNAAs at or Near Normal Levels • Adjuvant Therapy, Target Cognitive Improvements Mammalian System L Transporters Specific for LNAAs TransporterExpressionAmino AcidsTransported LAT-1 Li (fetal), BM, Br, Pl, Te L-I-V-F-Y-W-M-H LAT-2 Je, Ile, Ki, Pl, Br, Te, Sp L-F-W-T-N-I-C-S-Y-V-Q LAT-3 Pa, Li (fetal, adult), SM L-I-V-F LAT-4 Pl, Ki, Leuc L-F-I-M

  3. Non-Physiological Amino Acids A=Norleucine B=2-Aminoisobutyrate C=N-Methyl-2-aminoisobutyrate D=2-aminonorbornane-2-carboxylic acid Only NL previously used in a mammalian system Km values of LNAAs for LAT(s) may lead to NPAA concentrations that selectively lower Phe while minimally altering other LNAAs

  4. Brain Amino Acid Transport Systems • ~ Amino Acid Specificity • Considerable Overlap • Glutamine (Q): Numerous • Na Dependent/Independent • A ~ Smaller Amino Acids • L ~ Larger Amino Acids

  5. Approach • Dietary Administration-Clinical Relevance • Control Nitrogen Load with Casein • Monitor Brain LNAAs and Monoamines • Monitor Behavior/Movement in Future • Blood Chemistries (Safety) • Assess Effects on Nitrogen Load • Develop Methods to Quantify NPAAs

  6. LNAA Metabolic Roles

  7. PilotStudies-Effect on Phe/Tyr Phenylalanine Tyrosine

  8. Results for Monoamines Serotonin Dopamine

  9. Additional LNAA Outcomes Tryptophan Total Branched Chain AAs

  10. Effects on 1-Methyl Transfer Methionine SAMe

  11. Conclusions • Proof-of-Principle: Feasibility • Phe Reduction with NL, NB and MAIB • Other LNAA Effects: Lower Levels of NL and NB • Movement Effects of 3-5% NL Prominent • First Use of These in an Murine PKU Model • MAIB is a Selective A System Inhibitor • Can Clearly Reduce Phe, However • Not Previously Documented • More Benign Effects than 5% NL, 0.5% NB

  12. Goals in Future Studies • Different Concentrations of NPAAs • Combinatorial Administration (BBB-Gut) • NPAA Characterization in High/Low Protein • Address Variability in Some LNAA Levels • Evaluate Method of Sacrifice • Characterize Behavior during NPAA Intervention

  13. Acknowledgements Colleagues/Funding • Alliance Support • Kara Vogel • Brandi Wasek • ErlandArning • Terry Bottiglieri • R01 HD 58553 • U54 DK 83916

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