Pah enu2 Mice Relevance to PKU Therapy Mike Gibson Professor and Head Section of Clinical Pharmacology Washington State University WSU Spokane College of Pharmacy Spokane WA Disclosures None ID: 998640
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1. Non-Physiological Amino Acid (NPAA) Therapy in Pahenu2 MiceRelevance to PKU TherapyMike Gibson, Professor and HeadSection of Clinical PharmacologyWashington State University (WSU) SpokaneCollege of Pharmacy, Spokane WA Disclosures: None
2. Rationale and GoalsTo Selectively Lower Brain Phenylalanine NPAAs targeting L and A systems (BBB and gut)Maintain Other LNAAs at or Near Normal LevelsAdjuvant Therapy, Target Cognitive Improvements Mammalian System L Transporters Specific for LNAAs Transporter Expression Amino 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 AcidsA=Norleucine B=2-Aminoisobutyrate C=N-Methyl-2-aminoisobutyrate D=2-aminonorbornane-2-carboxylic acidOnly NL previously usedin a mammalian systemKm 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. ApproachDietary Administration-Clinical RelevanceControl Nitrogen Load with CaseinMonitor Brain LNAAs and MonoaminesMonitor Behavior/Movement in FutureBlood Chemistries (Safety)Assess Effects on Nitrogen LoadDevelop Methods to Quantify NPAAs
6. LNAA Metabolic Roles
7. Pilot Studies-Effect on Phe/TyrPhenylalanineTyrosine
8. Results for MonoaminesSerotoninDopamine
9. Additional LNAA OutcomesTryptophanTotal Branched Chain AAs
10. Effects on 1-Methyl TransferMethionineSAMe
11. ConclusionsProof-of-Principle: FeasibilityPhe Reduction with NL, NB and MAIBOther LNAA Effects: Lower Levels of NL and NBMovement Effects of 3-5% NL ProminentFirst Use of These in an Murine PKU ModelMAIB is a Selective A System InhibitorCan Clearly Reduce Phe, HoweverNot Previously DocumentedMore Benign Effects than 5% NL, 0.5% NB
12. Goals in Future StudiesDifferent Concentrations of NPAAsCombinatorial Administration (BBB-Gut)NPAA Characterization in High/Low ProteinAddress Variability in Some LNAA LevelsEvaluate Method of SacrificeCharacterize Behavior during NPAA Intervention
13. AcknowledgementsColleagues/FundingAlliance SupportKara VogelBrandi WasekErland ArningTerry BottiglieriR01 HD 58553U54 DK 83916