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Highlights from PKU: Advancing the dream - 2018 NPKUA Conference, July 5-8, Atlanta, GA USA

Highlights from PKU: Advancing the dream - 2018 NPKUA Conference, July 5-8, Atlanta, GA USA
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)


Resource type



human amnion epithelial cells
future therapies



The National PKU Alliance (USA) held our biannual meeting in Atlanta, Georgia in July 2018 - the tenth anniversary year of the organization’s founding. The history of PKU discovery and treatment were presented as central topics in celebration of our tenth anniversary, but the future of novel therapies for PKU was also featured. Scientists from both academia and industry around the world were invited to present updates on their PKU-related research through a combination of panel discussions, concurrent workshops, and poster sessions. We heard research updates from NPKUA-funded researchers as well as plans for clinical trials of novel PKU therapeutics from industry partners.

Geir Ivar Følling Elgjo, the grandson of Asbjørn Følling, provided an inspiring, personal family story regarding the discovery of PKU. His remarkable memoire was followed by a promising perspective from Betsy Bogard, a consultant to NPKUA, on the future of drug development for PKU. She outlined the efforts of nearly twenty different academic labs and industry partners who are pursuing novel treatments for PKU. The two presentations in juxtaposition were as two bookends displaying the past and future of PKU and provided a fitting introduction to the science to be presented later in the conference.

NPKUA funded research

NPKUA provides research funds to established investigators primarily to evaluate potential novel treatments for PKU but also to support the career development of pre- and postdoctoral researchers. Several NPKUA awardees provided updates on their research at the meeting.

Katherine Durrer, a postdoctoral fellow in the laboratory of Dr Mike Allen at the University of North Texas Health Science Center, has been working for several years on the development of a probiotic, Lactobacillus acidophilus, that expresses phenylalanine ammonia lyase (PAL). Her proposal is to provide this probiotic orally with food and that the bacteria will metabolize dietary phenylalanine (Phe) to trans-cinnamic acid and ammonia. She has partnered with biotech company Trayer Therapeutics to produce the probiotic under GMP conditions and to begin preclinical studies that would enable an Investigational New Drug application.

Roberto Gramignoli, postdoctoral researcher from the Stephen Strom lab at the Karolinska Institute, Stockholm, Sweden, described his ongoing work in the characterization of human amnion epithelial cells (hAEC) for use in cellular therapy.

Their unique immunologic properties allow hAEC to be transplanted into non-allogeneic individuals without the threat of rejection. In animal models, hAEC transplanted into liver can differentiate into hepatocytes and provide key missing enzymes. Dr Gramignoli has learned that hAEC express key epitopes (HLA-Ig, CD45, CD55, CD59, ecto-nucleotidases, and embryonic stem cell markers) that protect the cells from immunologic rejection and provide them with pluripotency for differentiation into various cell types. His group is pursuing regulatory permission to transplant hAEC into humans with a variety of genetic and acquired liver conditions, including PKU.

Professor Eileen Jaffe from Fox Chase Cancer Center, Philadelphia, PA, reviewed her outstanding work using crystallography of the phenylalanine hydroxylase (PAH) complex to explore the PAH enzymatic mechanism. Her group continues to make strides in understanding how PAH mutations destabilize the complex and how various drugs might act as chaperones to stabilize PAH.

Professor Robert Nicholls, University of Pittsburgh, and his postdoctoral fellow, Dr Erik Koppes provided an update on the PAH-deficient mini-swine model. They continue to characterize the single hyperphenylalaninemic animal in existence and are attempting to establish a breeding colony.

Daelyn Richards, a graduate student in Cary Harding’s lab at Oregon Health & Science University, Portland, OR, summarized her recent success using CRISPR/Cas9-mediated gene editing to correct hyperphenylalaninemia in neonatal Pahenu2 mice, a model of human PKU. In this work, she used two separate adeno-associated virus serotype 8 (AAV8) vectors to express Cas9 nuclease and to deliver the appropriately targeted guide RNA and PAH exon 7 repair template to hyperphenylalaninemic newborn Pahenu2/enu2 mice. She discovered that a second treatment with AAV vectors prior to weaning, along with administration of vanillin, a chemical inhibitor of nonhomologous end joining, were necessary to achieve a sufficient frequency of homologous recombination with the repair template in order to restore physiologically relevant levels of liver PAH activity and cause correction of blood Phe concentrations in the mice.


Industry partners

Dr Aoife Brennan, Chief Medical Officer of Synlogic, presented preclinical data on a PAL-expressing Escherichia coli probiotic that has been developed for the treatment of PKU. Enteral administration of the active probiotic to Pahenu2 mice led to detectable production of trans-cinnamic acid and a reduction in plasma Phe. The company has initiated a Phase 1/2 clinical trial to evaluate the safety and efficacy of this treatment approach in adults with PKU.

Rubius Therapeutics has developed PAL-expressing red blood cells produced from erythropoietic stem cells in culture. Dr Chris Carpenter proposed that these cells, derived from a blood type O negative donor, could be periodically and repetitively transfused into an individual with PKU as a method for clearing blood Phe. Plans for preclinical and clinical trials were presented.

Gjalt Huisman, PhD, Vice President of Biotherapeutics at Codexis, Inc., presented their preclinical data on a variant PAL enzyme that has been optimized for use as an orally administered therapeutic for PKU. The enzyme has been formulated to be tolerant to the low pH of the stomach and to digestive enzymes in the intestine. Administration of the drug to nonhuman primates was associated with a sustained decrease in plasma Phe. Nestlé has licensed the drug and is planning clinical trials.

Dr Albert Seymour from Homology Medicines reviewed results of AAV-mediated liver-directed gene therapy in the Pahenu2 mouse using their proprietary AAV-HSC vector system. They have explored both gene addition, expressing the human PAH cDNA from a liver specific promoter in adult Pahenu2 mice, but have also used their vector to facilitate homologous recombination of the cDNA into the murine PAH gene between the promoter and exon 1. In the latter approach, the cDNA is expressed from the native PAH promoter. The company plans to apply within the next year for regulatory permission to take their gene addition AAV vector into clinical trial in adults with PKU.

Awards and celebrations

The final evening of the conference witnessed a joyous and emotional celebration of a milestone in PKU treatment and of several important individuals to PKU history. PalynziqÔ(pegvaliase) completed its Phase 3 clinical trial and was approved for commercial use in adults with PKU in the US in May, 2018. The NPKUA chose this occasion to recognize the contributions of Christineh Sarkissian, PhD and Ray Stevens, PhD in the preclinical development of recombinant PAL as potential therapy for PKU. Dr Sarkissian was the first to treat Pahenu2 mice with subcutaneous injections of recombinant PAL while working as a postdoctoral fellow in the laboratory of Professor Charles Scriver at McGill University. Dr Stevens, then at Scripps Institute, subsequently evaluated PAL from many different species, tested specific mutations to improve kinetic features, and altered the PEGylation profile to improve immunogenicity, all necessary to ultimately develop the clinical candidate drug. BioMarin Pharmaceutical Corporation was given special recognition for successfully carrying pegvaliase through clinical trials to FDA approval. The award was accepted by Elaina Jurecki on behalf of the company.

The evening’s celebrations were capped off with delivery of the PKU Hero Award to Dr Barbara Burton for her contributions to PKU care and research throughout her career. Finally, the NPKUA Pioneer Award was given posthumously to Dr Robert Guthrie for the development of the newborn screening test for PKU. The award was accepted by Patricia Guthrie.


The past and the future shared equal billing at the remarkable and joyously successful NPKUA 2018 conference. Important tributes to pioneers in PKU history and recent successes in PKU research were highlighted. The future of research into novel treatments for PKU appears particularly promising.

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