Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria

Longo, Nicola; Dimmock, David; Levy, Harvey L.; Viau, Krista; Bausell, Heather; Bilder, Deborah A.; Burton, Barbara K.; Gross, Christel; Northrup, Hope; Rohr, Fran; Sacharow, Stephanie; Sanchez‐Valle, Amarilis; Stuy, Mary; Thomas, Janet A.; Vockley, Jerry; Zori, Roberto T.; Harding, Cary O.

doi:10.1038/s41436-018-0403-z

Cited by 67 publications

(77 citation statements)

References 136 publications

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“…8 These abnormalities can include lower IQ, executive functioning deficits, and psychiatric disorders (anxiety and depression), with the incidence of deficits increasing with increased blood Phe concentration. [10][11][12] A recent US Food and Drug Administration (FDA)-approved enzyme substitution therapy (pegvaliase) for adults with uncontrolled hyperphenylalaninemia on a diet has revealed dramatic improvements in blood Phe management [13][14][15][16] but is associated with a significant incidence of immune-mediated hypersensitivity reactions against the foreign protein. Additionally, pegvaliase is not approved for use in individuals less than 18 years of age.…”

Section: Introductionmentioning

confidence: 99%

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Richards

Winn

Dudley

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Phenylketonuria (PKU) due to recessively inherited phenylalanine hydroxylase (PAH) deficiency results in hyperphenylalaninemia, which is toxic to the central nervous system. Restriction of dietary phenylalanine intake remains the standard of PKU care and prevents the major neurologic manifestations of the disease, yet shortcomings of dietary therapy remain, including poor adherence to a difficult and unpalatable diet, an increased incidence of neuropsychiatric illness, and imperfect neurocognitive outcomes. Gene therapy for PKU is a promising novel approach to promote lifelong neurological protection while allowing unrestricted dietary phenylalanine intake. In this study, liver-tropic recombinant AAV2/8 vectors were used to deliver CRISPR/Cas9 machinery and facilitate correction of the Pah enu2 allele by homologous recombination. Additionally, a non-homologous end joining (NHEJ) inhibitor, vanillin, was co-administered with the viral drug to promote homologydirected repair (HDR) with the AAV-provided repair template. This combinatorial drug administration allowed for lifelong, permanent correction of the Pah enu2 allele in a portion of treated hepatocytes of mice with PKU, yielding partial restoration of liver PAH activity, substantial reduction of blood phenylalanine, and prevention of maternal PKU effects during breeding. This work reveals that CRISPR/Cas9 gene editing is a promising tool for permanent PKU gene editing.

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Section: Introductionmentioning

confidence: 99%

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Richards

Winn

Dudley

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…In recent years, alternative or complementary treatments were proposed. New protein substitutes, including large neutral amino acids (LNAA) and glycomacropeptide, and pharmacological treatments, such as sapropterin dihydrochloride (BH4) and phenylalanine ammonia lyase enzyme, were successful in the treatment of adult PKU patients [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study

Cazzorla¹,

Massa²,

Polo³

et al. 2019

Nutrients

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The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.

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“…Many clinical trial patients achieved sustained reductions in phenylalanine levels [47] Pegvaliase appears to be effective in lowering phenylalanine levels for people regardless of with PAH deficiency phenotypes [46]. Longo et al developed recommendations for treating adults with pegvaliase, and there is a need for long-term research on the safety, dosing, and management of patients using pegvaliase in this newly approved treatment [50].…”

Section: Pegvaliasementioning

confidence: 99%

Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe

Lowe

DeLuca

Arnold

2020

Orphanet J Rare Dis

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Background Individuals with phenylalanine hydroxylase (PAH) deficiency lack an enzyme needed to metabolize the amino acid, phenylalanine. This leads to an increase of phenylalanine in the blood, which is associated with changes in cognitive and psychological functioning. Skilled clinical management is essential for preventing complications and providing comprehensive care to patients. In the last decade, the American College of Genetics and Genomics (ACMG) and a group of European experts developed separate guidelines to provide recommendations for the management and care of persons with PAH deficiency. The purpose of this paper was to compare and contrast these guidelines in order to understand the different approaches to PAH deficiency care. Methods We examined the procedures used to develop both guidelines, then evaluated key areas in PAH deficiency care which included screening, diagnostic approaches, dietary treatment (initiation and duration), ongoing phenylalanine level/ nutritional monitoring, neurocognitive screening, adherence issues in treatment, and special populations (women and maternal PKU, late or untreated PAH deficiency, and transitioning to adult services). We conducted a scoping review of four key topics in PAH deficiency care to explore recent research studies performed since the publication of the guidelines. Results The ACMG and European expert group identified limited numbers of high quality studies to use as evidence for their recommendations. The ACMG and European guidelines had many similarities in their respective approaches PAH deficiency care and recommendations for the diagnosis, treatment, and management for persons with PAH deficiency. There were also a number of differences between the guidelines regarding the upper range for phenylalanine levels in adolescents and adults, the types of instruments used and frequency of neuropsychiatric examinations, and monitoring of bone health. Treatment adherence can be associated with a number of challenges, such as aversions to medical foods and formulas, as well as factors related to educational, social, and psychosocial issues. From the scoping review, there were many new studies addressing issues in treatment and management including new research on sapropterin adherence and increased dietary protein tolerance and pegvaliase on the reduction in phenylalanine levels and hypersensitivity reactions. Conclusions In the last decade, ACMG and European experts developed comprehensive guidelines for the clinical management of phenylalanine hydroxylase deficiency. The guidelines offered background and recommendations for clinical care of patients with PAH deficiency throughout the lifespan. New research evidence is available and updates to guidelines can keep pace with new developments. Evidence-based guidelines for diagnosis and treatment are important for providing expert care to patients.

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Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria

Cited by 67 publications

References 136 publications

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study

Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe

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