Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self‐complementary adeno‐associated virus vector

Yagi, Hiroya; Ogura, Tsuyoshi; Mizukami, Hiroaki; Urabe, Masashi; Hamada, Hiromi; Yoshikawa, Hiroyuki; Ozawa, Keiya; Kume, Akihiro

doi:10.1002/jgm.1543

Cited by 44 publications

(31 citation statements)

References 37 publications

(60 reference statements)

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“…Some mild neurocognitive symptoms, cost, difficulty of long-term compliance, and risk of nutritional deficiencies are recurrently cited to illustrate the need of alternative therapies that have been emerging over the last decade: nanotechnologies for PAH delivery, gene therapy, large neutral aminoacids, cofactor BH4 supplementation, and chaperone therapy (12,23,24) PKU is an ideal model for liver cell therapy, as this liver monogenic metabolic disease is believed to be curable with a low threshold of liver repopulation estimated at 5%-10% in the murine PKU model Pah enu2 (25,26). The current study demonstrates the acquisition of PAH metabolic activity during in vitro hepatogenic differentiation and makes ADHLSC promising for treating PKU.…”

Section: Discussionmentioning

confidence: 99%

Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase

Baruteau¹,

Nyabi

Najimi

et al. 2014

Journal of Pediatric Endocrinology and Metabolism

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Phenylketonuria (PKU) is one of the most prevalent inherited metabolic diseases and is accountable for a severe encephalopathy by progressive intoxication of the brain by phenylalanine. This results from an ineffective L-phenylalanine hydroxylase enzyme (PAH) due to a mutated phenylalanine hydroxylase (PAH) gene. Neonatal screening programs allow an early dietetic treatment with restrictive phenylalanine intake. This diet prevents most of the neuropsychological disabilities but remains challenging for lifelong compliance. Adult-derived human liver progenitor cells (ADHLPC) are a pool of precursors that can differentiate into hepatocytes. We aim to study PAH expression and PAH activity in a differenciated ADHLPC. ADHLPC were isolated from human hepatocyte primary culture of two different donors and differenciated under specific culture conditions. We demonstrated the high expression of PAH and a large increase of PAH activity in differenciated LPC. The age of the donor, the cellular viability after liver digestion and cryopreservation affects PAH activity. ADHLPC might therefore be considered as a suitable source for cell therapy in PKU.

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Section: Discussionmentioning

confidence: 99%

Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase

Baruteau¹,

Nyabi

Najimi

et al. 2014

Journal of Pediatric Endocrinology and Metabolism

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“…Significantly, intraperitoneal injection of scAAV8 encoding murine PAH into a PKU mouse model caused reduction in blood Phe to near normal levels. Importantly, this complete phenotypic correction was seen in mice of both genders and lasted more than one year 118 .…”

Section: Rare Disease and Current Raav Pre-clinical And Clinical Smentioning

confidence: 93%

Recombinant adeno-associated virus vectors in the treatment of rare diseases

Hastie

Samulski

2015

Expert Opinion on Orphan Drugs

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Introduction An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use. Areas covered In this review the biology of AAV and our ability to generate disease-specific variants is summarized. Limitations of current therapy are reviewed, with an emphasis on immune detection of virus, viral tropism and tissue targeting, and limitations of gene expression. Information for this review was found using PubMed and clinicaltrials.gov. Expert opinion Currently the scope of clinical trials of AAV gene therapy is concentrated in an array of phase I/II safety trials with less than two dozen rare diseases featured. Pre-clinical, translational studies are expanding in number as developments within the last decade have made generation of improved AAV vectors available to more researchers. Further, one bottleneck that is being overcome is the availability of disease models, which will allow for improved preclinical testing and advancement of AAV to more clinical applications.

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“…The AAV-2 were prepared as described previously54. They were produced in HEK293 cells using a helper-virus-free system, and purified twice with CsCl 2 density gradients and titrated by Q-polymerase chain reaction (PCR).…”

Section: Methodsmentioning

confidence: 99%

Distinct roles for primate caudate dopamine D1 and D2 receptors in visual discrimination learning revealed using shRNA knockdown

Takaji

Takemoto

Yokoyama³

et al. 2016

Sci Rep

Self Cite

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The striatum plays important motor, associative and cognitive roles in brain functions. However, the rodent dorsolateral (the primate putamen) and dorsomedial (the primate caudate nucleus) striatum are not anatomically separated, making it difficult to distinguish their functions. By contrast, anatomical separation exists between the caudate nucleus and putamen in primates. Here, we successfully decreased dopamine D1 receptor (D1R) or D2R mRNA expression levels selectively in the marmoset caudate using shRNA knockdown techniques, as determined using positron emission tomography imaging with specific D1R and D2R ligands and postmortem in situ hybridization analysis. We then conducted a voxel-based correlation analysis between binding potential values of PET imaging and visual discrimination learning task performance in these genetically modified marmosets to find a critical role for the caudate D2R but no apparent role for the caudate D1R. This latter finding challenges the current understanding of the mechanisms underlying D1R activation in the caudate.

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Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self‐complementary adeno‐associated virus vector

Cited by 44 publications

References 37 publications

Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase

Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase

Recombinant adeno-associated virus vectors in the treatment of rare diseases

Distinct roles for primate caudate dopamine D1 and D2 receptors in visual discrimination learning revealed using shRNA knockdown

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