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  • Writer's pictureN-of-1 Hub

Personalised clinical trials for people with Phenylketonuria

N-of-1 Hub is excited to be working with the University of Southern California on a series of N-of-1 trials to see whether large neutral amino acids (LNAAs) improve neurocognitive symptoms in adults with Phenylketonuria.


What is Phenylketonuria?

Patients with Phenylketonuria (PKU) are born with a deficiency in the activity of a liver enzyme which converts phenylalanine (Phe) to tyrosine, resulting in two pathological states: high blood Phe and low blood tyrosine. High blood Phe blocks lower levels of tyrosine and other large neutral amino acids (LNAAs) for a shared transporter from blood to brain. Multiple downstream effects of high brain Phe and low non-Phe LNAAs include neurotoxicity and inadequate synthesis of cerebral proteins and neurotransmitters. Blood-brain transport of Phe has been found to be highly variable, translating to heterogeneous clinical outcomes across individual patients, especially adults. Risks of harmful effects of brain Phe are monitored by regular assessments of blood Phe, the primary surrogate biomarker for PKU. Standard care for patients with PKU is a Phe-restricted diet which reduces natural dietary protein by 70-90% from the typical diet. People with PKU use a special medical protein formula which contains all essential dietary amino acids except Phe.


Example of low protein dinner for PKU adult. Photo provided by Frances Grove Hurst


















What is the clinical problem?

3 in 4 people with PKU maintain target blood phenylalanine levels to age twelve, with normal neurocognitive outcomes. But by adulthood, 75% of patients don’t achieve the target levels. More than half of adults with PKU have clinically significant brain symptoms which may impact quality of life. The PKU diet + medical foods (LNAAs) protects the developing brain of infants and children with PKU from irreversible intellectual disability. But how to treat adult PKU patients is uncertain. Maria Depenweiller a PKU patient advocate says: “I can get my blood levels to target, but it is a considerably bigger effort than my everyday diet and for what reason? I don’t feel any better. It’s lots of effort to maintain it…no one trained us to pay attention to certain symptoms; it’s all personal trial and error.” There is a need to personalize dietary treatment for each adult patient, to identify the most effective balance of phenylalanine and other LNAAs. N-of-1 trials may play an important role for the PKU community.


What are N-of-1 trials?

N-of-1 trials use the patient as their own control determine whether a treatment is effective for them. These study designs are often mistaken for “qualitative” or “descriptive” case studies, but they are prospectively designed quantitative studies designed to rigorously collect and analyse data from an individual. They provide more reliable conclusions than the “trial and error” approach that is commonly used to determine the best treatment for a patient in practice.


Associate Professor Jane Nikles, Director of N-of-1 Hub, explains, “Further value can be obtained through pooling the data from a series of N-of-1 trials. Pooled N-of-1 trials are well suited to rare diseases because they can provide rigorous information with a small number of patients. Pooled N-of-1 trials often need smaller numbers of patients to participate than the number needed for standard clinical trials.”


N-of-1 trials to test LNAAs in adults with PKU

Anne Prince (U.S. genetic metabolic research dietitian) states, "There is a relatively urgent need to re-evaluate the PKU diet for ways it could be modified or individualized, which would improve quality of life and that can be implemented rather quickly. We aim to evaluate effect of additional dietary LNAAs on symptom management in individual adults with PKU. N-of-1 individualised randomized controlled trials provide the highest level of scientific evidence about the effectiveness of a treatment for an individual.”


Dr Shoji Yano, Associate Professor of Clinical Pediatrics and Medicine and Division Head of Genetics, Keck School of Medicine, adds, “We hope that additional dietary LNAAs will improve effectiveness of the PKU diet to manage symptoms and improve quality of life for those with PKU. We will also find out for which participants LNAAs are effective.”


Dr Yano, Anne and other members of their team, including dieticians Kathryn Mosely and Kirsten Ahring, co-designed the PKU N-of-1 trials with N-of-1 Hub. The study data is managed and analysed by N-of-1 Hub. The study is funded by the National PKU Alliance and recruitment of participants has commenced.


N-of-1 Hub is a consulting company that specialises in designing, conducting and analysing personalised clinical studies using single-case designs. N-of-1 Hub also offers data management and analysis services and customised training workshops.


For more information about N-of-1 Hub, and to discuss your study needs, please contact us


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