Converting an injectable protein therapeutic into an oral form: Phenylalanine ammonia lyase for phenylketonuria

Kang, Taewook; Wan, Lin; Sarkissian, Christineh N.; Gámez, Alejandra; Scriver, Charles R.; Stevens, Raymond C.

doi:10.1016/j.ymgme.2009.09.002

Cited by 61 publications

(55 citation statements)

References 17 publications

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“…A multi-center Phase 2 clinical trial to assess the safety and efficacy of multiple, repetitive rAvPAL-PEG injections is currently underway. Meanwhile, efforts to develop an effective orally administered rAvPAL-PEG have also been initiated [86]. …”

Section: Phenylalanine Ammonia Lyase (Pal)mentioning

confidence: 99%

Up to date knowledge on different treatment strategies for phenylketonuria

Bélanger-Quintana

Burlina

Harding

et al. 2011

Molecular Genetics and Metabolism

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Dietary management for phenylketonuria was established over half a century ago, and has rendered an immense success in the prevention of the severe mental retardation associated with the accumulation of phenylalanine. However, the strict low-phenylalanine diet has several shortcomings, not the least of which is the burden it imposes on the patients and their families consequently frequent dietary non-compliance. Imperfect neurological outcome of patients in comparison to non-PKU individuals and nutritional deficiencies associated to the PKU diet are other important reasons to seek alternative therapies. In the last decade there has been an impressive effort in the investigation of other ways to treat PKU that might improve the outcome and quality of life of these patients. These studies have lead to the commercialization of sapropterin dihydrochloride, but there are still many questions regarding which patients to challenge with sapropterin what is the best challenge protocol and what could be the implications of this treatment in the long-term. Current human trials of PEGylated phenylalanine ammonia lyase are underway, which might render an alternative to diet for those patients non-responsive to sapropterin dihydrochloride. Preclinical investigation of gene and cell therapies for PKU is ongoing. In this manuscript, we will review the current knowledge on novel pharmacologic approaches to the treatment of phenylketonuria.

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Section: Phenylalanine Ammonia Lyase (Pal)mentioning

confidence: 99%

Up to date knowledge on different treatment strategies for phenylketonuria

Bélanger-Quintana

Burlina

Harding

et al. 2011

Molecular Genetics and Metabolism

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“…Gastric pH has a range between 1.5 and 2, and intestinal pH between 6 and 7.5, depending on dietary factors (37). As Phe enters enterocirculation, enzyme development eff orts should give priority to oral formulations containing entrapped PAL, which enable the release of Phe from bloodstream into the gastrointestinal tract where it is metabolized but not reabsorbed (38). We therefore measured PAL activity of C. fruticulosa in artifi cial gastric and intestinal fl uids.…”

Section: Resultsmentioning

confidence: 99%

Biochemical Evaluation of Phenylalanine Ammonia Lyase (PAL) from Endemic Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria (PKU)

Şirin¹,

Aydaş²,

Aslım³

2016

Food Technol. Biotechnol.

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SummaryEnzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9±0.1) U/ mg, with the optimum pH, temperature and buff er (Tris-HCl and l-phenylalanine) concentration levels of pH=8.8, 37 °C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purifi cation of the enzyme by 1.87-fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and aft er purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products.

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“…There is also a danger that interactions between polymer carriers and proteins will lead to proteins' denaturation. It is worth noting that PEGylation of proteins and DNA polyplexes reduces denaturation, degradation and immunogenicity of these compounds [102][103][104][105][106][107][108][109][110][111].…”

Section: Discussionmentioning

confidence: 99%

Progress in Nanoparticulate Systems for Peptide, Proteins and Nucleic Acid Drug Delivery

Słomkowski¹,

Gosecki

2011

CPB

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Progress in many therapies, in particular in the therapies based on peptides, proteins and nucleic acids used as bioactive compounds, strongly depends on development of appropriate carriers which would be suitable for controlled delivery of the intact abovementioned compounds to required tissues, cells and intracellular compartments. This review presents last ten years' achievements and problems in development and application of synthetic polymer nanoparticulate carriers for oral, pulmonary and nasal delivery routes of oligopeptides and proteins. Whereas some traditional synthetic polymer carriers are only briefly recalled the main attention is concentrated on nanoparticles produced from functional copolymers mostly with hydroxyl, carboxyl and amino groups, suitable for immobilization of targeting moieties and for assuring prolonged circulation of nanoparticles in blood. Formulations of various nanoparticulate systems are described, including solid particles, polymer micelles, nanovesicles and nanogels, especially systems allowing drug release induced by external stimuli. Discussed are properties of these species, in particular stability in buffers and models of body fluids, loading with drugs and with drug models, drug release processes and results of biological studies. There are also discussed systems for gene delivery with special attention devoted to polymers suitable for compacting nucleic acids into nanoparticles as well as the relations between chemical structure of polymer carriers and ability of the latter for crossing cell membranes and for endosomal escape.

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Converting an injectable protein therapeutic into an oral form: Phenylalanine ammonia lyase for phenylketonuria

Cited by 61 publications

References 17 publications

Up to date knowledge on different treatment strategies for phenylketonuria

Up to date knowledge on different treatment strategies for phenylketonuria

Biochemical Evaluation of Phenylalanine Ammonia Lyase (PAL) from Endemic Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria (PKU)

Progress in Nanoparticulate Systems for Peptide, Proteins and Nucleic Acid Drug Delivery

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