L-Phenylalanine for Phenylketonuria Carriers

(Phe for Me Trial)

Overseen By Justine R Keathley, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Guelph

Must not be taking: Monoamine oxidase inhibitors

Disqualifiers: PKU, Neurodegenerative conditions, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a clinical intervention study of PKU carriers (cases) and non-carriers (controls). Upon completing the informed consent process, participants will complete baseline measures of chronic mental health prior to the intervention (PHQ-9, GAD-7, BIS-11). Participants will attend the Human Nutraceutical Research Unit (HNRU) at the University of Guelph, fasted, and first undergo baseline measures of cognition and acute mental health (mood) and provide samples or saliva, urine and dried blood spots to evaluate phenylalanine (Phe), tyrosine (Tyr) and their metabolites (PAH pathway functioning) as well as for genetic testing of the PAH gene. Participants will also complete a brief questionnaire which will include age, sex, ethnicity, income, weight and height (measured using a stadiometer and calibrated weigh scale), and confirmation that participants arrived to the lab fasted (i.e. have only had water to drink and no other foods/ beverages prior to analyses). Blood pressure and heart rate will also be measured at baseline. Following baseline tests, participants will consume a pure L-Phe supplement dosed at 100 mg/kg mixed with 125 mL of water and 125mL of orange juice. Blood pressure and heart rate will be repeated at 1-hour post-L-Phe consumption. Two-hours postprandial, participants will repeat the cognitive tests and acute mental health (mood) assessment, blood pressure and heart rate measurement and provide follow-up saliva, urine and dried blood spot samples. Participants will also be asked to report any side effects they experienced with the L-Phe consumption.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking a monoamine oxidase inhibitor anti-depressant.

Is L-Phenylalanine safe for humans?

Research on treatments involving phenylalanine ammonia-lyase (PAL) suggests that it is generally safe, as studies in animals showed no harmful changes in blood cells or other adverse reactions. However, more studies are needed to confirm long-term safety in humans. ^{1 2 3 4 5}

How is the drug L-Phenylalanine different from other treatments for phenylketonuria?

L-Phenylalanine is unique because it is being studied for its potential to inhibit tryptophan transport, which may help address serotonin depletion in phenylketonuria, unlike traditional treatments that focus on dietary restrictions. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for adults who either carry the PKU gene or do not, and are comfortable fasting in the morning. It's not for those with melanoma, hypertension, liver or kidney disease, pregnant/breastfeeding women, individuals over 150 kg, parents of children with PKU, people with severe cognitive conditions like Alzheimer's or on certain antidepressants.

Inclusion Criteria

I either have or do not have PKU.

I am 18 years old or older.

You are able to abstain from consumption prior to the study.

Exclusion Criteria

You are allergic to oranges or citrus fruits.

I have been diagnosed with high blood pressure.

I have been diagnosed with liver disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline Assessment

Participants complete baseline measures of chronic mental health and provide samples for genetic testing and baseline health metrics

1 day

1 visit (in-person)

Intervention

Participants consume L-Phe supplement and undergo repeated cognitive and health assessments

1 day

1 visit (in-person)

Follow-up

Participants are monitored for side effects and changes in health metrics post-intervention

0-3 hours post L-Phe consumption

Treatment Details

Interventions

• L-Phenylalanine

Trial Overview The study tests how a supplement called L-Phenylalanine (L-Phe) affects mental health and cognition in both carriers and non-carriers of PKU. Participants will take L-Phe mixed with water and orange juice after fasting and undergo various health assessments before and after consumption.

Participant Groups

Group I: Genetic Carriers and Non-Carriers of PKU Experimental Treatment 1 Intervention

L-Phenylalanine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as L-Phenylalanine for:

• Dietary supplement
• Medical food for phenylketonuria management

Approved in European Union as L-Phenylalanine for:

• Dietary supplement
• Medical food for phenylketonuria management

Approved in Canada as L-Phenylalanine for:

• Dietary supplement
• Medical food for phenylketonuria management

Who Is Running the Clinical Trial?

University of Guelph

Lead Sponsor

Trials

87

Recruited

15,100+

Laval University

Collaborator

Trials

439

Recruited

178,000+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

Findings from Research

The hollow fiber enzyme-reactors with immobilized phenylalanine ammonia-lyase (PAL) were found to be safe for clinical use, as they did not affect blood cell levels or increase blood urea nitrogen during a 2-hour application in animal models with high phenylalanine levels.

Repeated use of the PAL-reactors did not cause any adverse physiological or immunological reactions, suggesting they could effectively manage excess phenylalanine in individuals with phenylketonuria, especially during conditions like fever or pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo safety of hollow fiber enzyme-reactors with immobilized phenylalanine ammonia-lyase in a large animal model for phenylketonuria. Ambrus, CM., Sharma, SD., Horváth, C., et al.[2013]

In a study using the Pah(enu2/enu2) PKU mouse model, an oral enzyme substitution therapy with a modified phenylalanine ammonia lyase (PAL) significantly reduced plasma phenylalanine levels by approximately 40%, demonstrating its efficacy (p=0.0029).

The reduction in phenylalanine was dose- and loading-dependent, suggesting that more frequent and smaller doses could enhance treatment effectiveness, making oral PAL therapy a promising adjunct to dietary management for patients with phenylketonuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. Sarkissian, CN., Kang, TS., Gámez, A., et al.[2022]

A short-term double-blind placebo-controlled study demonstrated that large neutral amino acids (LNAA) significantly reduced blood phenylalanine (Phe) concentrations by an average of 39% in patients with phenylketonuria (PKU).

This study provides proof of principle for the use of orally administered LNAA as a potential treatment for lowering blood Phe levels in PKU, although further long-term studies are necessary to assess the treatment's safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. Matalon, R., Michals-Matalon, K., Bhatia, G., et al.[2022]

Pegvaliase, an injectable enzyme therapy for phenylketonuria (PKU), can cause Type III hypersensitivity reactions, particularly during the initial induction and titration phases, but these reactions tend to decrease over time with continued treatment due to factors like antibody affinity maturation.

To manage hypersensitivity adverse events (HAEs) effectively, it is recommended to use a slow induction and titration regimen, premedication with H1-receptor antagonists, and to ensure patients carry auto-injectable adrenaline, which can improve tolerability and safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy. Hausmann, O., Daha, M., Longo, N., et al.[2020]

Oral administration of microencapsulated yeast phenylalanine ammonia-lyase (PAL) significantly reduced plasma phenylalanine levels by 51.3% in genetically mutated PKU mice over 23 days, demonstrating its potential as a treatment for phenylketonuria.

The study found that while some mice achieved target phenylalanine levels, the initial seven days showed no significant decrease, possibly due to the health condition of the mice or the need for higher PAL doses compared to previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy in ENU2 phenylketonuric mice using oral microencapsulated phenylalanine ammonia-lyase: a preliminary report. Safos, S., Chang, TM.[2013]

L-phenylalanine, which accumulates in patients with phenylketonuria, competitively inhibits the uptake of tryptophan in rat-brain synaptosomes, suggesting a direct interaction at the cellular level.

This inhibition of tryptophan transport may lead to decreased serotonin levels, which could explain the neurological symptoms associated with phenylketonuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition by L-phenylalanine of tryptophan transport by synaptosomal plasma membrane vesicles: implications in the pathogenesis of phenylketonuria. Herrero, E., Aragon, MC., Gimenez, C., et al.[2019]

Using proton magnetic resonance spectroscopy (1H MRS), researchers successfully monitored brain phenylalanine (Phe) concentrations in healthy subjects after standardized oral Phe loading, demonstrating that Phe levels peak about 1 hour post-load.

This study establishes a method for detecting and analyzing Phe transport across the blood-brain barrier, which is crucial for understanding the pathogenesis of phenylketonuria (PKU) and could help in comparing healthy individuals with PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy. Pietz, J., Lutz, T., Zwygart, K., et al.[2019]

The study developed a new treatment for phenylketonuria (PKU) by using genetically engineered Lactococcus lactis to produce phenylalanine ammonia-lyase (PAL), which significantly reduced plasma phenylalanine levels in hyperphenylalaninemia rats.

Among the two expression vectors used, pNZ8048 showed higher PAL expression and more effective results in lowering phenylalanine levels compared to pMG36e, suggesting it may be a better option for future PKU therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study on a novel strategy to treatment of phenylketonuria. Liu, J., Jia, X., Zhang, J., et al.[2019]

In a study using rats with phenylketonuria (PKU), the administration of Phenylalanine ammonia lyase (PAL) loaded artificial cells significantly reduced intestinal phenylalanine levels compared to a phenylalanine-free diet.

The presence of high concentrations of phenylalanine in the intestinal lumen was found to decrease the transport of other neutral amino acids into the plasma, highlighting the impact of phenylalanine on amino acid absorption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of oral administration of artificial cells immobilized phenylalanine ammonia-lyase on intestinal amino acids of phenylketonuric rats. Bourget, L., Chang, TM.[2019]

Three innovative strategies were developed to enhance the oral delivery of phenylalanine ammonia lyase (PAL) for treating phenylketonuria, addressing challenges like low intestinal pH and proteolytic digestion.

These strategies included modifying the enzyme to improve resistance to proteases, using a silica matrix for better protection during digestion, and PEGylating the enzyme to reduce inactivation, which could lead to more effective oral therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria. Kang, TS., Wang, L., Sarkissian, CN., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

In vivo safety of hollow fiber enzyme-reactors with immobilized phenylalanine ammonia-lyase in a large animal model for phenylketonuria. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy in ENU2 phenylketonuric mice using oral microencapsulated phenylalanine ammonia-lyase: a preliminary report. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Inhibition by L-phenylalanine of tryptophan transport by synaptosomal plasma membrane vesicles: implications in the pathogenesis of phenylketonuria. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Study on a novel strategy to treatment of phenylketonuria. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Effects of oral administration of artificial cells immobilized phenylalanine ammonia-lyase on intestinal amino acids of phenylketonuric rats. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria. [2021]