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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how the supplement L-Phenylalanine (L-Phe) affects individuals who carry the gene for Phenylketonuria (PKU) and those who do not. Researchers aim to determine if L-Phe influences mental health and cognitive function, including thinking and memory. Participants will undergo mood and cognitive testing and provide saliva and urine samples before and after taking the supplement. Eligible participants are those comfortable with fasting, who either carry or do not carry the PKU gene, but do not have PKU or other serious health conditions such as liver disease or high blood pressure.

As an unphased trial, this study offers participants the chance to contribute to foundational research that could lead to new insights into mental health and cognitive function.

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.

What prior data suggests that L-Phenylalanine is safe for PKU carriers?

Research shows that L-Phenylalanine is generally safe for most people. However, individuals with phenylketonuria (PKU) can face health risks if phenylalanine accumulates in their bodies due to improper processing. For those without PKU, L-Phenylalanine is usually well-tolerated.

In studies on L-Phenylalanine, participants have reported few side effects. Researchers closely monitor for any negative reactions, such as mood changes or blood pressure shifts. If side effects occur, they are usually mild, like minor digestive issues.

This trial will monitor the effects of L-Phenylalanine on both individuals with and without PKU. Participants will take the supplement and report any side effects. This careful monitoring ensures safety and checks for any unusual responses. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard of care for phenylketonuria (PKU), which typically involves a strict low-phenylalanine diet and specialized medical formulas, L-Phenylalanine offers a unique approach by directly addressing phenylalanine levels in carriers of the condition. Researchers are excited about this treatment because it could provide a new way to manage phenylalanine levels without the need for restrictive dietary measures. This could lead to improved quality of life for carriers who might otherwise face dietary challenges. Additionally, by focusing on carriers, this treatment might offer insights into managing PKU more broadly, potentially reducing the burden on patients and their families.

What evidence suggests that L-Phenylalanine might be an effective treatment for phenylketonuria?

Research has shown that people carrying the gene for phenylketonuria (PKU) might experience challenges with thinking skills, such as lower IQ and slower memory and processing speed. Their bodies process phenylalanine (Phe), a substance found in many foods, differently. Early studies suggest that managing Phe levels could enhance thinking skills and overall quality of life for those with PKU. However, limited evidence exists on whether extra L-Phenylalanine can aid these improvements. This trial will examine the effects of L-Phenylalanine supplementation on mental health and thinking skills in both genetic carriers and non-carriers of PKU to better understand and manage Phe levels. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

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.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07220265

Impact of Phenylalanine Elevations on Brain and Cognition ... The main questions it aims to answer are: Do PKU carriers experience prolonged elevations in brain Phe levels following oral ingestion of ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK535378/

Phenylketonuria - StatPearls - NCBI Bookshelf Phenylketonuria (PKU) is an inborn error of metabolism (IEM) most often caused by missense mutations in the gene encoding phenylalanine hydroxylase (PAH).

3. karger.com karger.com/lfg/article/17/1/102/910844/Are-Carriers-Unaffected-A-Literature-Review-of

Are Carriers Unaffected? A Literature Review of Metabolic ... Early research has found associations between PKU carrier status and lower IQs as well as decreased executive functioning, memory, processing speed, and ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1098360022010632

ACMG Systematic Evidence Review Phenylalanine ... The results indicate Phe-lowering drugs can improve QoL and neurodevelopmental outcomes in patients compared with medical diet alone. Our findings support a ...

5. ojrd.biomedcentral.com ojrd.biomedcentral.com/articles/10.1186/s13023-025-03840-y

Current state of the treatment landscape of phenylketonuria As, to date, there is insufficient evidence concerning the safety and efficacy of the administration of an additional dose of LNAAs and studies ...

6. mayoclinic.org mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302

Phenylketonuria (PKU) - Symptoms and causes A dangerous buildup of phenylalanine can develop when a person with PKU eats protein-rich foods, such as milk, cheese, nuts or meat, or grains ...

7. nichd.nih.gov nichd.nih.gov/health/topics/factsheets/pku

Phenylketonuria (PKU) - Health - NICHD The amount of phenylalanine that is safe to consume differs for each person. Therefore, a person with PKU needs to work with a health care professional to ...

8. osmosis.org osmosis.org/answers/phenylalanine

Phenylalanine: What Is It, Function, Phenylketonuria, and ... Phenylalanine can pose severe health risks for individuals with phenylketonuria (PKU), a genetic disorder that causes phenylalanine and its ...