non-physiological amino acid (npaa) therapy in pah enu2 mice relevance to pku therapy

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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

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