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Cited by 135Virus-based gene therapy researchRNA Interference and Gene DeliveryMetabolism and Genetic Disorders

Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡

Open access
Paulk, Nicole K., Wursthorn, Karsten, Wang, Zhongya, Finegold, Milton J., Kay, Mark A., Grompe, Markus·2010·Hepatology
DOI 10.1002/hep.23481PMC PMC3136243
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Abstract

UNLABELLED: Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation-based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10(-3) were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. CONCLUSION: AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.

AI snapshot

Written from the paper’s full text.

TL;DR

AAV-mediated gene repair corrected the point mutation in the *Fah* gene in a mouse model of hereditary tyrosinemia type I, in both neonatal and adult mice. AAV8 was faster and more efficient than AAV2, and corrected hepatocytes expanded to repopulate the liver and reverse the metabolic disease.

Key findings

  • AAV-Fah serotypes 2 and 8 achieved hepatic gene repair in *Fah*^5981SB mice; correction frequencies reached up to 10^-3, and AAV8 was superior to AAV2.
  • In neonatal time-course studies, AAV8-Fah produced up to 1/180 FAH+ hepatocytes within the first week, whereas AAV2-Fah showed little detectable FAH expression in the first 7 days and increased by week 2; no FAH+ hepatocytes were detected in control-vector mice.
  • AAV8-Fah showed a linear dose response from 3 × 10^8 to 3 × 10^11 vg, with the highest dose producing the greatest repair; AAV2-Fah showed no significant change across doses.
  • Adult AAV8-Fah treatment (1 × 10^11 vg) produced clinical improvement and FAH+ repopulation, with near-complete correction of AST and bilirubin versus controls (P < 0.05); random integration averaged 0.01/dGE (1%) in corrected hepatocytes.

Methods

  • The *Fah*^5981SB mouse model of hereditary tyrosinemia type I was used; NTBC blocked toxic metabolite accumulation, and NTBC withdrawal selected for corrected FAH+ hepatocytes.
  • AAV vectors of serotypes 2 and 8 carried a 4.5-kb genomic *Fah* sequence centered on the point mutation; neonatal mice received intravenous facial vein injection and adult mice received tail vein injection, with doses ranging from 3 × 10^8 to 3 × 10^11 vg.
  • Correction was assessed by FAH immunohistochemistry, *Fah* RT-PCR, serum liver function tests, quantitative PCR for random integration, partial hepatectomy, and serial transplantation; significance was tested with a two-tailed Student t-test (P < 0.05).

Limitations

  • The paper states that the low frequency of correction in vivo remains a major handicap and is still too low to be therapeutic for many diseases; the HTI model is an exception because corrected hepatocytes have a selective growth advantage.
  • The paper states that if correction frequencies were increased even 10-fold, they would become clinically relevant for a broader range of diseases, implying current efficiency limits broader applicability.
  • Evident from the text: the therapeutic strategy depends on strong in vivo selection of corrected cells, so generalizability to diseases without such selection is limited; the work is in mice, with no human data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/hep.23481

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    FAH immunohistochemistry showed >50% FAH+ hepatocytes in section overviews.

    “FAH immunohistochemistry showed >50% FAH+ hepatocytes in section overviews (Fig. 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    AAV-treated mice began to stabilize in weight at 8 weeks after treatment, suggesting the onset of sufficient liver function.

    “AAV-treated mice began to stabilize in weight at 8 weeks after treatment, suggesting the onset of sufficient liver function.”
    Quote in the paperSubstantial claim
  • Findingown data

    FAH immunohistochemistry from livers of serial transplant recipients had extensive hepatocellular FAH staining, further demonstrating stability of the gene repair.

    “FAH immunohistochemistry from livers of serial transplant recipients had extensive hepatocellular FAH staining, further demonstrating stability of the gene repair (Fig. 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Differences in serum AST and bilirubin levels were significant (P < 0.05).

    “Differences in serum AST and bilirubin levels were significant (P < 0.05).”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    The average random integration frequency in corrected hepatocytes was 0.01/dGE (1%).

    “resulting in an average random integration frequency of 0.01/dGE (1%) in corrected hepatocytes.”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    The numbers of detectable liver nodules ranged from 21-47 per 50 mm2 section in treated mice and were never detected in controls.

    “The numbers of detectable liver nodules ranged from 21–47 per 50 mm2 section in treated mice and were never detected in controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Successful gene repair was observed with both AAV2 and AAV8, but was more efficient with AAV8.

    “Successful gene repair was observed with both serotypes but was more efficient with AAV8.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both neonatal and adult mice treated with AAV-Fah, gene repair restored proper gene and protein expression and cured the underlying HTI phenotype.

    “In both neonatal and adult mice treated with AAV-Fah, gene repair restored proper gene and protein expression and cured the underlying HTI phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The initial gene repair frequency ranged from 1/6,300 to 1/11,600 hepatocytes and was within the expected range from previous experiments where selection with NTBC did not apply.

    “After correction, the initial gene repair frequency ranged from 1/6,300 to 1/11,600 hepatocytes and was within the expected range from previous experiments15 where selection with NTBC did not apply.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Miller DG Wang PR Petek LM Hirata RK Sands MS Russell DW Gene targeting in vivo by adeno-associated virus vectors Nat Biotechnol 2006 24 1022 1026 16878127 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Correction frequencies of up to 10−3 were achieved and were highly reproducible within typical dose ranges.

    “Correction frequencies of up to 10−3 were achieved and highly reproducible within typical dose ranges.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adult Fah5981SB mice treated with AAV8-Fah showed clinical improvement and repopulation with FAH+ hepatocytes, whereas all mice in the control group had to be euthanized and showed no hepatic repopulation.

    “Mice treated with AAV8-Fah showed clinical improvement and repopulation with FAH+ hepatocytes (Fig. 5A), whereas all mice in the control group had to be euthanized and showed no hepatic repopulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In AAV8-Fah treated mice, correction frequencies declined with time and stabilized after 4 weeks.

    “Correction frequencies declined with time and stabilized after 4 weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our work tested a range of AAV doses from 1011 to 108 vg and was able to demonstrate correction at all doses administered.

    “Finally, our work tested a range of AAV doses from 1011 to 108 vg and was able to demonstrate correction at all doses administered.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The clonal expansion of corrected hepatocytes was able to reverse the tyrosinemic phenotype and was highly reproducible.

    “The clonal expansion of corrected hepatocytes was able to reverse the tyrosinemic phenotype and was highly reproducible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Week two showed an increase in Fah expression that remained stable until week four in AAV2-treated mice.

    “Week two showed an increase in Fah expression that remained stable until week four.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    AAV2-treated mice had little detectable Fah expression within the first seven days, supporting the fact that AAV2 uncoats more slowly than AAV8.

    “In contrast, AAV2-treated mice had little detectable Fah expression within the first seven days, supporting the fact that AAV2 uncoats more slowly than AAV8.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The biology of AAV8 and AAV2 differed considerably in terms of gene targeting.

    “Interestingly, the biology of these two serotypes differed considerably in terms of gene targeting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Serial transplant recipients had successful engraftment and displayed clinical improvement, whereas untransplanted controls showed continuous weight loss and died.

    “Serial transplant recipients had successful engraftment and displayed clinical improvement, whereas untransplanted controls showed continuous weight loss and died.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AAV8-Fah displayed a linear dose response over the range of doses administered where the highest doses administered produced the greatest gene repair.

    “In general, AAV8-Fah displayed a linear dose response over the range of doses administered (Fig. 4) where the highest doses administered produced the greatest gene repair.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The frequency of randomly integrated hAAT ranged from 0 (undetectable) to 0.06/dGE and averaged 0.005/dGE.

    “The frequency of randomly integrated hAAT ranged from 0 (undetectable) to 0.06/dGE and averaged 0.005/dGE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Serial transplantation was possible without difficulty and serially reconstituted animals had normal hepatic function.

    “Serial transplantation was possible without difficulty and serially reconstituted animals had normal hepatic function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NTBC treatment at 4 mg/mL rescues the phenotype and prevents acute hepatocellular and renal injury.

    “NTBC treatment at 4 mg/mL rescues the phenotype and prevents acute hepatocellular and renal injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Grompe M Lindstedt S al-Dhalimy M Kennaway NG Papaconstantinou J Torres-Ramos CA Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I Nat Genet 1995 10 453 460 7545495

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisereasoning

    Gene repair restores gene function within the context of all endogenous regulatory elements, thereby eliminating potential problems with inadequate or inappropriate expression.

    “gene repair restores gene function within the context of all endogenous regulatory elements, thereby eliminating potential problems with inadequate or inappropriate expression.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Numerous in vitro studies have shown AAV capable of correcting various types of mutations (insertions, deletions, substitutions) by vector-mediated homologous recombination.

    “Numerous in vitro studies have shown AAV capable of correcting various types of mutations (insertions, deletions, substitutions) by vector-mediated homologous recombination.16,17”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Inoue N Dong R Hirata RK Russell DW Introduction of single base substitutions at homologous chromosomal sequences by adeno-associated virus vectors Mol Ther 2001 3 526 530 11319913 source

      Not checked in the free run.

    • cites [17] Inoue N Hirata RK Russell DW High-fidelity correction of mutations at multiple chromosomal positions by adeno-associated virus vectors J Virol 1999 73 7376 7380 10438827 PMC104264 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    AAV vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential.

    “Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Hendrie PC Russell DW Gene targeting with viral vectors Mol Ther 2005 12 9 17 15932801 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Gene repair is best suited to correct point-mutation-based diseases that need only one or few nucleotides corrected to restore normal gene expression.

    “Gene repair is best suited to correct point-mutation–based diseases that need only one or few nucleotides corrected to restore normal gene expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Single-stranded AAV genomes modulate gene repair by integrating site-specifically via homologous recombination and targeting only the disease-causing mutation for replacement with wild-type sequence.

    “Single-stranded AAV genomes modulate gene repair by integrating site-specifically via homologous recombination and targeting only the disease-causing mutation for replacement with wild-type sequence.19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Parekh-Olmedo H Ferrara L Brachman E Kmiec EB Gene therapy progress and prospects: targeted gene repair Gene Ther 2005 12 639 646 15815682 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Point mutations are the most frequent genetic abnormality and source of acquired genetic disease.

    “point mutations are the most frequent genetic abnormality and source of acquired genetic disease.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Bergeron B Case Studies in Genes and Disease 2004 1st ed. Philadelphia American College of Physicians Press

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Mice develop liver and renal disease within 10 days, which progresses to full end-stage liver disease and death within 6-8 weeks.

    “Mice develop liver and renal disease within 10 days, which progresses to full end-stage liver disease and death within 6–8 weeks.27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Grompe M Lindstedt S al-Dhalimy M Kennaway NG Papaconstantinou J Torres-Ramos CA Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I Nat Genet 1995 10 453 460 7545495

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In this model, repaired hepatocytes have a selective growth advantage and are able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease.

    “In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quantitation was performed by two separate, blinded investigators.

    “Quantitation was performed by two separate, blinded investigators.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Not all protein-coding genes have open reading frames small enough to fit within the low coding capacity of AAV (4.7 kb), so gene addition is not applicable for all disorders.

    “Not all protein-coding genes have open reading frames small enough to fit within the low coding capacity of AAV (4.7 kb), thus, this type of gene therapy is not applicable for all disorders.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Verma IM Somia N Gene therapy–promises, problems and prospects Nature 1997 389 239 242 9305836 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This point mutation creates a premature downstream stop codon and exon 8 loss, ultimately leading to formation of truncated, unstable FAH protein that is degraded.

    “This point mutation creates a premature downstream stop codon and exon 8 loss, ultimately leading to formation of truncated, unstable FAH protein that is degraded.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Culiat CT Klebig ML Liu Z Monroe H Stanford B Desai J Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7 Mamm Genome 2005 16 555 566 16180137 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Fah5981SB mouse is ideal to study gene repair because it is point-mutation-based and fully recapitulates the human disease on an accelerated time scale.

    “The Fah5981SB mouse is ideal to study gene repair, because it is point-mutation– based and fully recapitulates the human disease on an accelerated time scale.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Aponte JL Sega GA Hauser LJ Dhar MS Withrow CM Carpenter DA Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1 Proc Natl Acad Sci U S A 2001 98 641 645 11209059 PMC14641 source

      Not checked in the free run.

    • cites [26] Culiat CT Klebig ML Liu Z Monroe H Stanford B Desai J Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7 Mamm Genome 2005 16 555 566 16180137 source

      Not checked in the free run.

    • cites [27] Grompe M Lindstedt S al-Dhalimy M Kennaway NG Papaconstantinou J Torres-Ramos CA Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I Nat Genet 1995 10 453 460 7545495 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.

    “AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Few publications exist demonstrating repair in vivo, and they are hindered by targeting clinically irrelevant marker mutations in exogenously provided transgenes like GFP or LacZ.

    “Few publications exist demonstrating repair in vivo,39,40 and they are hindered by the fact that they target clinically irrelevant marker mutations in exogenously provided transgenes like green fluorescent protein (GFP) or LacZ.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Vijg J Dolle ME Martus HJ Boerrigter ME Transgenic mouse models for studying mutations in vivo: applications in aging research Mech Ageing Dev 1997 98 189 202 9352489 source

      Not checked in the free run.

    • cites [40] Nickerson HD Colledge WH A LacZ-based transgenic mouse for detection of somatic gene repair events in vivo Gene Ther 2004 11 1351 1357 15229632 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Our study establishes the utility of two different AAV serotypes (AAV8 and AAV2) for hepatic gene targeting of both adult and neonatal mice in vivo.

    “Our study establishes the utility of two different AAV serotypes (AAV8 and AAV2) for hepatic gene targeting of both adult and neonatal mice in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Targeting was confirmed by immunohistochemistry, RT-PCR, and functional measures of liver correction using serum liver function tests.

    “Targeting was confirmed by immunohistochemistry, RT-PCR, and functional measures of liver correction using serum liver function tests.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results conclusively demonstrate that emergence of FAH+ hepatocytes were neither due to spontaneous reversion, nor gene repair stimulated non-specifically by mere AAV transduction.

    “These results conclusively demonstrate that emergence of FAH+ hepatocytes were neither due to spontaneous reversion, nor gene repair stimulated non-specifically by mere AAV transduction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Gene repair frequencies of 10−2 would have therapeutic benefit in patients with hemophilia A.

    “For example, it has been predicted that gene repair frequencies of 10−2 would have therapeutic benefit in patients with hemophilia A.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Kay MA High K Gene therapy for the hemophilias Proc Natl Acad Sci U S A 1999 96 9973 9975 10468539 PMC33717

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different kinetics for the two serotypes have been described previously with gene addition approaches wherein higher doses of AAV correlated with higher levels of gene expression.

    “Different kinetics for the two serotypes have been described previously with gene addition approaches wherein higher doses of AAV correlated with higher levels of gene expression.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Thomas CE Storm TA Huang Z Kay MA Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors J Virol 2004 78 3110 3122 14990730 PMC353747 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In that study, a single point mutation in the β-glucuronidase gene was corrected at frequencies of 10−4 to 10−5 using AAV2 and AAV6 at 2 × 1011 to 6 × 1011 vg doses.

    “In that study, a single point mutation in the β-glucuronidase gene was corrected at frequencies of 10−4 to 10−5 using AAV2 and AAV6 at 2 × 1011 to 6 × 1011 vg doses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Miller DG Wang PR Petek LM Hirata RK Sands MS Russell DW Gene targeting in vivo by adeno-associated virus vectors Nat Biotechnol 2006 24 1022 1026 16878127 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several disorders in which selection has been shown include Fanconi's anemia, Wilson's disease, many bile-acid transporter defects, and junctional epidermolysis bullosa.

    “While this situation is an exception, there are several disorders in which selection has been shown, including Fanconi’s anemia,41 the copper storage disorder Wilson’s disease,42 many bile-acid transporter defects,43 and junctional epidermolysis bullosa44 to name a few.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Battaile KP Bateman RL Mortimer D Mulcahy J Rathbun RK Bagby G In vivo selection of wild-type hematopoietic stem cells in a murine model of Fanconi anemia Blood 1999 94 2151 2158 10477746 source

      Not checked in the free run.

    • cites [42] Allen KJ Cheah DM Wright PF Gazeas S Pettigrew-Buck NE Deal YH Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease J Gastroenterol Hepatol 2004 19 1283 1290 15482536 source

      Not checked in the free run.

    • cites [43] De Vree JM Ottenhoff R Bosma PJ Smith AJ Aten J Oude Elferink RP Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis Gastroenterology 2000 119 1720 1730 11113093 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The novel approach described herein can serve as a model for gene repair in any monogenic disease caused by point mutations.

    “Although these experiments focused on correcting the metabolic disease HTI, the novel approach described herein can serve as a model for gene repair in any monogenic disease caused by point mutations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    If correction frequencies were increased even 10-fold, they would become clinically relevant for an even broader range of diseases.

    “If correction frequencies were increased even 10-fold, they would become clinically relevant for an even broader range of diseases.”
    Quote in the paperNot a substantial claim
40 of 40

  • The authors state this as an assumption.

    The statistical comparisons using Student 2-tailed t-test assume equal variance.

    “Experimental results were analyzed for significance by applying a student 2-tailed t-test assuming equal variance.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NTBC is an inhibitor of the tyrosine catabolic pathway upstream of FAH.

    “2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)14 is an inhibitor of the tyrosine catabolic pathway upstream of FAH.”

    From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [14]

  • Following correction by CRISPR, liver cells expressing the Fah enzyme expand and repopulate the liver through their selective advantage.

    “Following correction by CRISPR, liver cells expressing the Fah enzyme, through their selective advantage, expand and repopulate the liver14.”

    From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [14]

  • Fahmut/mut mice need to be kept alive on NTBC-supplemented water to prevent toxin buildup and liver damage.

    “Fahmut/mut mice need to be kept alive on NTBC-supplemented water to prevent toxin buildup and liver damage14.”

    From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [14]

  • The expansion of corrected hepatocytes caused the widespread patches of Fah+ hepatocytes.

    “As shown in Fig. 1d and Supplementary Fig. 2, ABE generated widespread patches of Fah+ hepatocytes in the Fahmut/mut livers due to the expansion of corrected hepatocytes14.”

    From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [14]

  • The Fahmut/mut mouse model harbors a homozygous G•C to A•T point mutation in the last nucleotide of exon 8, resulting in exon skipping and loss of FAH protein.

    “The Fahmut/mut mouse model14, 15 harbors a homozygous G•C to A•T point mutation in the last nucleotide of exon 8, resulting in exon skipping and loss of FAH protein.”

    From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [14]

The citation lists haven’t been fetched yet

References 44 · Cited by 135

Authors
Paulk, N. K., Wursthorn, K., Wang, Z., Finegold, M. J., Kay, M. A., & Grompe, M.
Affiliations
  • Oregon Health & Science University (US)
  • Medizinische Hochschule Hannover (DE)
  • Texas Children's Hospital (US)
Corresponding author
Grompe, Markus
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-04
Volume
51
Issue
4
Pages
1200-1208
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.23481
PMC
PMC3136243
OpenAlex
W2056111824
Semantic Scholar
2164c7ccc849f25f5d97e3adf80c47edd1a6d3b2
Cited by
135
References
44
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 10 · 2022: 11 · 2021: 10 · 2020: 13 · 2019: 9 · 2018: 12 · 2017: 15 · 2016: 11 · 2015: 8 · 2014: 10 · 2013: 2 · 2012: 9
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1979 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (F31CA130116)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, R01-DK48252)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
adeno-associated virus vectors, gene repair, tyrosinemia type I, fumarylacetoacetate hydrolase, homologous recombination, AAV8, AAV2, targeted gene integration, liver-directed gene therapy, hepatocyte proliferation, metabolic liver disease
MeSH terms
Dependovirus, Animals, Disease Models, Animal, Genetic Vectors, Hydrolases, Mice, Inbred C57BL, Genetic Therapy, Tyrosinemias, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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