Mouse models of human phenylketonuria.

Shedlovsky, Alexandra; McDonald, J. David; Symula, Derek J.; Dove, William F.

doi:10.1093/genetics/134.4.1205

Cited by 219 publications

(55 citation statements)

References 27 publications

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“…This could be because plasma Phe levels were raised a bit more than intended (6.5 times normal, rather than < 5 times normal) or because the neurochemical effects of moderately elevated plasma Phe levels are not as localized as we have hypothesized. O ur lab is presently investigating this further with the genetic mouse model of PK U created by M cDonald & Shedlovsky (McDonald et al 1990;Shedlovsky et al 1993). These mice have a m utation of the gene that causes PK U in hum ans; these mice have a m utation of the gene homologous to the one that causes PK U in hum ans; these mice, too, are severely impaired in converting Phe to Tyr.…”

Section: An Anim Al M Od El Of M Ild C H R O N Ic Plasm a Ph E Ele V A T Io N Smentioning

confidence: 99%

Evidence for the importance of dopamine for prefrontal cortex functions early in life

Diamond

1996

Phil. Trans. R. Soc. Lond. B

130

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There is considerable evidence that dorsolateral prefrontal cortex subserves critical cognitive abilities even during early infancy and that improvement in these abilities is evident over roughly the next 10 years. We also know that (a) in adult monkeys these cognitive abilities depend critically on the dopaminergic projection to prefrontal cortex and (b) the distribution of dopamine axons within dorsolateral prefrontal cortex changes, and the level of dopamine increases, during the period that infant monkeys are improving on tasks that require the cognitive abilities dependent on prefrontal cortex. To begin to look at whether these cognitive abilities depend critically on the prefrontal dopamine projection in humans even during infancy and early childhood we have been studying children who we hypothesized might have a selective reduction in the dopaminergic innervation of prefrontal cortex and a selective impairment in the cognitive functions subserved by dorsolateral prefrontal cortex. These are children treated early and continuously for the genetic disorder, phenylketonuria (PKU). In PKU the ability to convert the amino acid, phenylalanine (Phe), into another amino acid, tyrosine (Tyr), is impaired. This causes Phe to accumulate in the bloodstream to dangerously high levels and the plasma level of Tyr to fall. Widespread brain damage and severe mental retardation result. When PKU is moderately well controlled by a diet low in Phe (thus keeping the imbalance between Phe and Tyr in plasma within moderate limits) severe mental retardation is averted, but deficits remain in higher cognitive functions. In a four-year longitudinal study we have found these deficits to be in the working memory and inhibitory control functions dependent upon dorsolateral prefrontal cortex in PKU children with plasma Phe levels 3-5 times normal. The fact that even infants showed these impairments suggests that dopaminergic innervation to prefrontal cortex is critical for the proper expression of these abilities even during the first year of life. To test the hypothesis about the underlying biological mechanism we have created the first animal model of early and continuously treated PKU. As predicted, the experimental animals had reduced levels of dopamine and the dopamine metabolite, homovanillic acid (HVA), in prefrontal cortex and showed impaired performance on delayed alternation, a task dependent on prefrontal cortex function. Noradrenaline levels were unaffected; however some reduction in serotonin levels and in dopamine levels outside the prefrontal cortex was found. If prefrontal cortex functions are vulnerable in children with a moderate plasma Phe:Tyr imbalance because of the special properties of the dopamine neurons that project to prefrontal cortex, then other dopamine neurons that share those same properties should also be vulnerable in these children. The dopamine neurons in the retina share these properties (i.e. unusually high firing and dopamine turnover rates), and we have found that PKU children with plasma Phe leve...

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Section: An Anim Al M Od El Of M Ild C H R O N Ic Plasm a Ph E Ele V A T Io N Smentioning

confidence: 99%

Evidence for the importance of dopamine for prefrontal cortex functions early in life

Diamond

1996

Phil. Trans. R. Soc. Lond. B

130

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“…These result in a lowering of functional PAH enzyme levels, leading to toxic accumulation of phenylalanine (L-Phe) and its byproducts in the blood. The Pah enu2 mouse model for PKU carries a homozygous point mutation on exon 7 (c.835T>C; p.F263S), resulting in abnormally high blood L-Phe levels of ~2000 µmol/L (36). While correction of the mutation using cytidine BEs has led to a reduction in blood L-Phe levels below the therapeutic threshold and full restoration of the PKU phenotype (13,16), product purity of the edited locus was relatively low, with more than half of the edited alleles containing either bystander or indel mutations (13).…”

Section: Subhead 5: Establishment Of Prime Editing Strategies To Correct the Pah Enu2 Allelementioning

confidence: 99%

Treatment of a metabolic liver disease by in vivo prime editing in mice

Boeck

Rothgangl

Villiger

et al. 2021

Preprint

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Prime editing is a highly versatile CRISPR-based genome editing technology with the potential to correct the vast majority of pathogenic mutations. However, correction of a disease phenotype in vivo in somatic tissues has not been demonstrated thus far. Here, we establish proof-of-concept for in vivo prime editing and repair the metabolic liver disease phenylketonuria (PKU) in mice. We first developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain of the reverse transcriptase (PE2-deltaRnH), and a linker- and NLS-optimized intein-split PE construct (PE2 p.1153) for delivery by adeno-associated virus (AAV) vectors. Systemic dual AAV-mediated delivery of this variant into the liver of neonatal mice enabled installation of a transversion mutation at the Dnmt1 locus with an average efficiency of 15%, and delivery of unsplit PE2-deltaRnH using human adenoviral vector 5 (AdV5) further increased editing rates to 58%. PE2-deltaRnH-encoding AdV5 was also used to correct the disease-causing mutation of the phenylalanine hydroxylase (Pah)enu2 allele in phenylketonuria (PKU) mice with an average efficiency of 8% (up to 17.3%), leading to therapeutic reduction of blood phenylalanine (L-Phe) levels. Our study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications.

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“….It may lower phenylalanine blood levels by 30-40% or more (Sarkissian et al, 2005). The original trials were on the Pah enu2/enu2 mouse model (Shedlovsky et al, 1993). One of the early problems was the development of immunogenicity.…”

Section: Large Neutral Amino Acids (Lnaa)mentioning

confidence: 99%

Latest Findings in Intellectual and Developmental Disabilities Research

Tan¹

2012

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Professor Dr Üner Tan, born in 1937, is a Turkish neuroscientist and evolutionary biologist, best known for his discovery in 2005 and study of human quadrupedalism with a cognitive decline (Uner Tan syndrome). He taught at various universities in Germany and Turkey until his retirement in 2004. Today, he is working as a senior scientist at Cukurova University in Turkey. Tan is the honorary member of the Turkish Academy of Sciences, and has won numerous awards, including the Science Award from the Turkish Scientific and Technical Council, the Einstein and Nobel Medals for Science and Peace from the Albert Einstein Foundation in the USA, and the Gold Record for Brain Research at the American Biographical Institute. Tan's scientific studies include the physiology and pharmacology of the spino-cerebral motor systems, reflexes in human neonates, cerebral lateralization, intelligence, handedness, finger-length patterns, blood sex hormone levels, and Uner Tan syndrome (quadrupedalism and cognitive decline). Tan has published around 200 papers with nearly 2000 citations since 1966.

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Mouse models of human phenylketonuria.

Cited by 219 publications

References 27 publications

Evidence for the importance of dopamine for prefrontal cortex functions early in life

Evidence for the importance of dopamine for prefrontal cortex functions early in life

Treatment of a metabolic liver disease by in vivo prime editing in mice

Latest Findings in Intellectual and Developmental Disabilities Research

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