FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2031170457> ?p ?o ?g. }

• W2031170457 endingPage "S83" @default.
• W2031170457 startingPage "S82" @default.
• W2031170457 abstract "The common human genetic disorder Phenylketonuria (PKU) is primarily caused by defects in the enzyme phenylalanine hydroxylase (PAH). An animal model for PKU, the BTBR Pahenu2 mouse, has a missense mutation (F263S) that inactivates PAH; the mouse exhibits classic PKU, with elevated blood Phe levels, cognitive deficiencies, and maternal PKU syndrome. We have corrected both the serum Phe levels and maternal PKU in Pahenu2 mice using recombinant AAV vectors containing the mouse PAH gene. Although successful, unusually high vector doses were needed to achieve normal serum Phe levels. More critically, there was a gradual loss of therapeutic effect 20-24 weeks after vector delivery in many animals, particularly females. This was accompanied by changes in liver morphology suggestive of increased metabolic activity.Pahenu2 mice express reduced levels of a mutant PAH protein. The normal enzyme is a tetramer and we have reported evidence fordominant-negative interactions between endogenous mutant subunits and vector-introduced functional subunits. Possible approaches to combating a dominant-negative interaction include the production of ribozymes targeting the endogenous mutant mRNA and expression of modified forms of PAH protein that do not form tetramers. We have shown that a serotype 2 AAV vector expressing both a ribozyme directed against the mouse PAH mRNA and a ribozyme-resistant form of mPAH (mPAH-Hd) were effective at reducing serum Phe levels. We now show that modified forms of the PAH enzyme can, in certain cases, reduce dominant-negative interference. A vector expressing an obligate dimer form of mPAH was still subject to negative interference, indicating this inhibition occurs at the level of the monomer-monomer interaction. We will present in vitro and in vivo data examining the effectiveness of both a monomeric PAH enzyme as well as chimeric enzymes expressing a mouse PAH catalytic core linked to the rat tyrosine hydroxylase tetramerization domain in reducing dominant-negative interactions with missense subunits. The common human genetic disorder Phenylketonuria (PKU) is primarily caused by defects in the enzyme phenylalanine hydroxylase (PAH). An animal model for PKU, the BTBR Pahenu2 mouse, has a missense mutation (F263S) that inactivates PAH; the mouse exhibits classic PKU, with elevated blood Phe levels, cognitive deficiencies, and maternal PKU syndrome. We have corrected both the serum Phe levels and maternal PKU in Pahenu2 mice using recombinant AAV vectors containing the mouse PAH gene. Although successful, unusually high vector doses were needed to achieve normal serum Phe levels. More critically, there was a gradual loss of therapeutic effect 20-24 weeks after vector delivery in many animals, particularly females. This was accompanied by changes in liver morphology suggestive of increased metabolic activity. Pahenu2 mice express reduced levels of a mutant PAH protein. The normal enzyme is a tetramer and we have reported evidence fordominant-negative interactions between endogenous mutant subunits and vector-introduced functional subunits. Possible approaches to combating a dominant-negative interaction include the production of ribozymes targeting the endogenous mutant mRNA and expression of modified forms of PAH protein that do not form tetramers. We have shown that a serotype 2 AAV vector expressing both a ribozyme directed against the mouse PAH mRNA and a ribozyme-resistant form of mPAH (mPAH-Hd) were effective at reducing serum Phe levels. We now show that modified forms of the PAH enzyme can, in certain cases, reduce dominant-negative interference. A vector expressing an obligate dimer form of mPAH was still subject to negative interference, indicating this inhibition occurs at the level of the monomer-monomer interaction. We will present in vitro and in vivo data examining the effectiveness of both a monomeric PAH enzyme as well as chimeric enzymes expressing a mouse PAH catalytic core linked to the rat tyrosine hydroxylase tetramerization domain in reducing dominant-negative interactions with missense subunits." @default.
• W2031170457 created "2016-06-24" @default.
• W2031170457 creator A5000550102 @default.
• W2031170457 creator A5023571704 @default.
• W2031170457 creator A5062727443 @default.
• W2031170457 creator A5066423578 @default.
• W2031170457 creator A5068431367 @default.
• W2031170457 creator A5079575942 @default.
• W2031170457 creator A5083084332 @default.
• W2031170457 date "2006-01-01" @default.
• W2031170457 modified "2023-10-17" @default.
• W2031170457 title "214. Dominant-Negative Interference in the Pahenu2 Mouse: Modified Forms of PAH" @default.
• W2031170457 doi "https://doi.org/10.1016/j.ymthe.2006.08.239" @default.
• W2031170457 hasPublicationYear "2006" @default.
• W2031170457 type Work @default.
• W2031170457 sameAs 2031170457 @default.
• W2031170457 citedByCount "0" @default.
• W2031170457 crossrefType "journal-article" @default.
• W2031170457 hasAuthorship W2031170457A5000550102 @default.
• W2031170457 hasAuthorship W2031170457A5023571704 @default.
• W2031170457 hasAuthorship W2031170457A5062727443 @default.
• W2031170457 hasAuthorship W2031170457A5066423578 @default.
• W2031170457 hasAuthorship W2031170457A5068431367 @default.
• W2031170457 hasAuthorship W2031170457A5079575942 @default.
• W2031170457 hasAuthorship W2031170457A5083084332 @default.
• W2031170457 hasBestOaLocation W20311704571 @default.
• W2031170457 hasConcept C104317684 @default.
• W2031170457 hasConcept C143065580 @default.
• W2031170457 hasConcept C16613235 @default.
• W2031170457 hasConcept C181199279 @default.
• W2031170457 hasConcept C185592680 @default.
• W2031170457 hasConcept C207009774 @default.
• W2031170457 hasConcept C2777431362 @default.
• W2031170457 hasConcept C501734568 @default.
• W2031170457 hasConcept C515207424 @default.
• W2031170457 hasConcept C55493867 @default.
• W2031170457 hasConcept C67705224 @default.
• W2031170457 hasConcept C75563809 @default.
• W2031170457 hasConcept C76346623 @default.
• W2031170457 hasConcept C86803240 @default.
• W2031170457 hasConceptScore W2031170457C104317684 @default.
• W2031170457 hasConceptScore W2031170457C143065580 @default.
• W2031170457 hasConceptScore W2031170457C16613235 @default.
• W2031170457 hasConceptScore W2031170457C181199279 @default.
• W2031170457 hasConceptScore W2031170457C185592680 @default.
• W2031170457 hasConceptScore W2031170457C207009774 @default.
• W2031170457 hasConceptScore W2031170457C2777431362 @default.
• W2031170457 hasConceptScore W2031170457C501734568 @default.
• W2031170457 hasConceptScore W2031170457C515207424 @default.
• W2031170457 hasConceptScore W2031170457C55493867 @default.
• W2031170457 hasConceptScore W2031170457C67705224 @default.
• W2031170457 hasConceptScore W2031170457C75563809 @default.
• W2031170457 hasConceptScore W2031170457C76346623 @default.
• W2031170457 hasConceptScore W2031170457C86803240 @default.
• W2031170457 hasLocation W20311704571 @default.
• W2031170457 hasOpenAccess W2031170457 @default.
• W2031170457 hasPrimaryLocation W20311704571 @default.
• W2031170457 hasRelatedWork W175288621 @default.
• W2031170457 hasRelatedWork W1968150876 @default.
• W2031170457 hasRelatedWork W1986076152 @default.
• W2031170457 hasRelatedWork W2043693641 @default.
• W2031170457 hasRelatedWork W2258430434 @default.
• W2031170457 hasRelatedWork W2265453606 @default.
• W2031170457 hasRelatedWork W2350102540 @default.
• W2031170457 hasRelatedWork W2385938607 @default.
• W2031170457 hasRelatedWork W2393441490 @default.
• W2031170457 hasRelatedWork W2469776549 @default.
• W2031170457 hasVolume "13" @default.
• W2031170457 isParatext "false" @default.
• W2031170457 isRetracted "false" @default.
• W2031170457 magId "2031170457" @default.
• W2031170457 workType "article" @default.