Non-Physiological Amino Acid (NPAA) Therapy in 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
Slide 2
Rationale and Goals To Selectively Lower Brain Phenylalanine 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 Adjuvant Therapy,
Target Cognitive Improvements Mammalian System L Transporters
Specific for LNAAs TransporterExpression 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
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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 K m values of
LNAAs for LAT(s) may lead to NPAA concentrations that selectively
lower Phe while minimally altering other LNAAs
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Brain Amino Acid Transport Systems ~ Amino Acid Specificity ~
Amino Acid Specificity Considerable Overlap Considerable Overlap
Glutamine (Q): Numerous Glutamine (Q): Numerous Na
Dependent/Independent Na Dependent/Independent A ~ Smaller Amino
Acids A ~ Smaller Amino Acids L ~ Larger Amino Acids L ~ Larger
Amino Acids
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Approach Dietary Administration-Clinical Relevance Dietary
Administration-Clinical Relevance Control Nitrogen Load with Casein
Control Nitrogen Load with Casein Monitor Brain LNAAs and
Monoamines Monitor Brain LNAAs and Monoamines Monitor
Behavior/Movement in Future Blood Chemistries (Safety) Blood
Chemistries (Safety) Assess Effects on Nitrogen Load Develop
Methods to Quantify NPAAs Develop Methods to Quantify NPAAs
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LNAA Metabolic Roles
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Pilot Studies-Effect on Phe/Tyr Phenylalanine Tyrosine
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Results for Monoamines SerotoninDopamine
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Additional LNAA Outcomes Tryptophan Total Branched Chain
AAs
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Effects on 1-Methyl Transfer MethionineSAMe
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Conclusions Proof-of-Principle: Feasibility 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 MAIB is a Selective A System Inhibitor Can Clearly
Reduce Phe, However Not Previously Documented More Benign Effects
than 5% NL, 0.5% NB
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Goals in Future Studies Different Concentrations of NPAAs
Different Concentrations of NPAAs Combinatorial Administration
(BBB-Gut) Combinatorial Administration (BBB-Gut) NPAA
Characterization in High/Low Protein NPAA Characterization in
High/Low Protein Address Variability in Some LNAA Levels Address
Variability in Some LNAA Levels Evaluate Method of Sacrifice
Evaluate Method of Sacrifice Characterize Behavior during NPAA
Intervention Characterize Behavior during NPAA Intervention
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Acknowledgements Colleagues/Funding Alliance Support Alliance
Support Kara Vogel Kara Vogel Brandi Wasek Brandi Wasek Erland
Arning Erland Arning Terry Bottiglieri Terry Bottiglieri R01 HD
58553 R01 HD 58553 U54 DK 83916 U54 DK 83916