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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. Rationale and Goals. - PowerPoint PPT Presentation
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Non-Physiological Amino Acid (NPAA) Therapy in Pahenu2 Mice
Relevance to PKU Therapy
Mike Gibson, Professor and HeadSection of Clinical Pharmacology
Washington State University (WSU) SpokaneCollege of Pharmacy, Spokane WA
Disclosures: None
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 LNAAsTransporter 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
Non-Physiological Amino Acids
A=Norleucine B=2-Aminoisobutyrate C=N-Methyl-2-aminoisobutyrate D=2-aminonorbornane-2-carboxylic acid
Only NL previously usedin a mammalian system
Km values of LNAAs for LAT(s) may lead to NPAA concentrations that selectively lower Phe while minimally altering other LNAAs
Brain Amino Acid Transport Systems
• ~ Amino Acid Specificity• Considerable Overlap• Glutamine (Q): Numerous• Na
Dependent/Independent• A ~ Smaller Amino Acids• L ~ Larger Amino Acids
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
LNAA Metabolic Roles
Pilot Studies-Effect on Phe/TyrPhenylalanine Tyrosine
Results for Monoamines
Serotonin Dopamine
Additional LNAA Outcomes
Tryptophan Total Branched Chain AAs
Effects on 1-Methyl Transfer
Methionine SAMe
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
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
AcknowledgementsColleagues/Funding
• Alliance Support• Kara Vogel• Brandi Wasek• Erland Arning• Terry Bottiglieri• R01 HD 58553• U54 DK 83916