Transcript Heritable Disorders of GABA (4-Aminobutyrate) Metabolism

Non-Physiological Amino Acid
enu2
(NPAA) Therapy in Pah
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
• 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
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
Non-Physiological Amino Acids
A=Norleucine
B=2-Aminoisobutyrate
C=N-Methyl-2aminoisobutyrate
D=2-aminonorbornane2-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
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/Tyr
Phenylalanine
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
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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
Acknowledgements
Colleagues/Funding
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Alliance Support
Kara Vogel
Brandi Wasek
Erland Arning
Terry Bottiglieri
R01 HD 58553
U54 DK 83916