Scholars@Duke
Karl-Dimiter Bissig

Karl-Dimiter Bissig

Chen Family Associate Professor of Pediatrics
Pediatrics, Medical Genetics

Scholarly Works

High-potency MyoAAV capsids enhanced skeletal muscle correction in a mouse model of GSD IIIa.

Journal article Mol Ther Methods Clin Dev · September 11, 2025 Glycogen storage disease type IIIa (GSD IIIa) affects multiple tissues, including liver, heart, and skeletal muscles. We recently reported that an adeno-associated virus serotype 9 vector expressing pullulanase, a bacterial glycogen debranching enzyme, dri ... Full text Open Access Link to item Cite

Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.

Journal article JCI Insight · September 9, 2025 Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompen ... Full text Link to item Cite

CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I.

Journal article JHEP Rep · April 2025 BACKGROUND & AIMS: The therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of ... Full text Link to item Cite

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Journal article Sci Transl Med · February 12, 2025 Homology-directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. He ... Full text Link to item Cite

Ex vivo gene editing and cell therapy for hereditary tyrosinemia type 1.

Journal article Hepatol Commun · May 1, 2024 BACKGROUND: We previously demonstrated the successful use of in vivo CRISPR gene editing to delete 4-hydroxyphenylpyruvate dioxygenase (HPD) to rescue mice deficient in fumarylacetoacetate hydrolase (FAH), a disorder known as hereditary tyrosinemia type 1 ... Full text Link to item Cite

A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

Journal article J Hepatol · April 2024 BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has develope ... Full text Link to item Cite

A humanized mouse model for adeno-associated viral gene therapy.

Journal article Nat Commun · March 4, 2024 Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg-/-/Rag2-/-/Fah-/-/A ... Full text Link to item Cite

Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model.

Journal article J Hepatol · February 2024 BACKGROUND & AIMS: Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this stud ... Full text Link to item Cite

Rescue of glutaric aciduria type I in mice by liver-directed therapies.

Journal article Sci Transl Med · April 19, 2023 Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabol ... Full text Link to item Cite

The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice.

Journal article Eur J Pharm Sci · February 1, 2023 Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be inv ... Full text Link to item Cite

Cyp1a2-knockout increases the systemic exposure of a serotonin and norepinephrine reuptake inhibitor duloxetine in mice.

Journal article FASEB J · May 2022 Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor for the treatment of major depressive disorder, mainly metabolized by CYP1A2 and CYP2D6 in human. Despite DLX has a good tolerance, serious adverse events (e.g., liver injury) have ... Full text Link to item Cite

Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice.

Journal article Drug Metab Dispos · February 2022 Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The me ... Full text Link to item Cite

Targeting the Apoa1 locus for liver-directed gene therapy.

Journal article Mol Ther Methods Clin Dev · June 11, 2021 Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent and broadly applicable while minimizing risks of off ... Full text Link to item Cite

A human liver chimeric mouse model for non-alcoholic fatty liver disease.

Journal article JHEP Rep · June 2021 BACKGROUND & AIMS: The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world's population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despi ... Full text Link to item Cite

A hepatitis B virus transgenic mouse model with a conditional, recombinant, episomal genome.

Journal article JHEP Rep · April 2021 BACKGROUND & AIMS: Development of new and more effective therapies against hepatitis B virus (HBV) is limited by the lack of suitable small animal models. The HBV transgenic mouse model containing an integrated overlength 1.3-mer construct has yielded cruc ... Full text Link to item Cite

Metabolic profiling of norepinephrine reuptake inhibitor atomoxetine.

Journal article Eur J Pharm Sci · October 1, 2020 Atomoxetine (ATX), a selective and potent inhibitor of the presynaptic norepinephrine transporter, is used mainly to treat attention-deficit hyperactivity disorder. Although multiple adverse effects associated with ATX have been reported including severe l ... Full text Link to item Cite

Generation of model tissues with dendritic vascular networks via sacrificial laser-sintered carbohydrate templates.

Journal article Nat Biomed Eng · September 2020 Sacrificial templates for patterning perfusable vascular networks in engineered tissues have been constrained in architectural complexity, owing to the limitations of extrusion-based 3D printing techniques. Here, we show that cell-laden hydrogels can be pa ... Full text Link to item Cite

Innovations, challenges, and minimal information for standardization of humanized mice.

Journal article EMBO Mol Med · July 7, 2020 Mice xenotransplanted with human cells and/or expressing human gene products (also known as "humanized mice") recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo c ... Full text Link to item Cite

Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex.

Journal article Cells · March 30, 2020 The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ... Full text Link to item Cite

Somatic Liver Knockout (SLiK): A Quick and Efficient Way to Generate Liver-Specific Knockout Mice Using Multiplex CRISPR/Cas9 Gene Editing.

Journal article Curr Protoc Mol Biol · March 2020 Somatic liver knockout (SLiK) is a method developed to rapidly generate a liver-specific knockout of one or several genes. This technique combines the strengths of CRISPR/Cas9 gene editing and hydrodynamic tail-vein injection, a simple in vivo method for t ... Full text Link to item Cite

Small Animal Models for Human Immunodeficiency Virus (HIV), Hepatitis B, and Tuberculosis: Proceedings of an NIAID Workshop.

Journal article Curr HIV Res · 2020 The main advantage of animal models of infectious diseases over in vitro studies is the gain in the understanding of the complex dynamics between the immune system and the pathogen. While small animal models have practical advantages over large animal mode ... Full text Link to item Cite

Using CRISPR/Cas9 to model human liver disease.

Journal article JHEP Rep · November 2019 CRISPR/Cas9 gene editing has revolutionised biomedical research. The ease of design has allowed many groups to apply this technology for disease modelling in animals. While the mouse remains the most commonly used organism for embryonic editing, CRISPR is ... Full text Link to item Cite

Rapid Disruption of Genes Specifically in Livers of Mice Using Multiplex CRISPR/Cas9 Editing.

Journal article Gastroenterology · December 2018 BACKGROUND & AIMS: Despite advances in gene editing technologies, generation of tissue-specific knockout mice is time-consuming. We used CRISPR/Cas9-mediated genome editing to disrupt genes in livers of adult mice in just a few months, which we refer to as ... Full text Link to item Cite

P450-Humanized and Human Liver Chimeric Mouse Models for Studying Xenobiotic Metabolism and Toxicity.

Journal article Drug Metab Dispos · November 2018 Preclinical evaluation of drug candidates in experimental animal models is an essential step in drug development. Humanized mouse models have emerged as a promising alternative to traditional animal models. The purpose of this mini-review is to provide a b ... Full text Link to item Cite

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension.

Journal article Am J Hum Genet · August 2, 2018 Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hyperten ... Full text Link to item Cite

HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice.

Journal article Cytotherapy · May 2018 BACKGROUND: Chronic hepatitis B virus (HBV) infection remains incurable. Although HBsAg-specific chimeric antigen receptor (HBsAg-CAR) T cells have been generated, they have not been tested in animal models with authentic HBV infection. METHODS: We generat ... Full text Link to item Cite

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma.

Journal article Commun Biol · 2018 Hepatoblastoma (HBL) is a pediatric liver cancer that affects children under the age of three. Reduction of tumor suppressor proteins (TSPs) is commonly seen in liver cancer. However, in our studies we find that aggressive, chemo-resistant HBLs exhibit an ... Full text Link to item Cite

A Novel Cell Line Based Orthotopic Xenograft Mouse Model That Recapitulates Human Hepatoblastoma.

Journal article Sci Rep · December 19, 2017 Currently, preclinical testing of therapies for hepatoblastoma (HB) is limited to subcutaneous and intrasplenic xenograft models that do not recapitulate the hepatic tumors seen in patients. We hypothesized that injection of HB cell lines into the livers o ... Full text Link to item Cite

In Situ Liver Expression of HBsAg/CD3-Bispecific Antibodies for HBV Immunotherapy.

Journal article Mol Ther Methods Clin Dev · December 15, 2017 Current therapies against hepatitis B virus (HBV) do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow ... Full text Link to item Cite

Erratum: A novel humanized mouse lacking murine p450 oxidoreductase for studying human drug metabolism.

Journal article Nat Commun · October 17, 2017 An incorrect version of the Supplementary Information was inadvertently published with this Article where the wrong file was included. The HTML has been updated to include the correct version of the Supplementary Information. ... Full text Link to item Cite

CRISPR/Cas9: at the cutting edge of hepatology.

Journal article Gut · July 2017 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome engineering has revolutionised biomedical science and we are standing on the cusp of medical transformation. The therapeutic potential of this technology is tremendous, however, ... Full text Link to item Cite

A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism.

Journal article Nat Commun · June 28, 2017 Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric liver ... Full text Link to item Cite

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease.

Journal article Sci Rep · March 16, 2017 Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to av ... Full text Link to item Cite

Differentiation of spontaneously contracting cardiomyocytes from non-virally reprogrammed human amniotic fluid stem cells.

Journal article PLoS One · 2017 Congenital heart defects are the most common birth defect. The limiting factor in tissue engineering repair strategies is an autologous source of functional cardiomyocytes. Amniotic fluid contains an ideal cell source for prenatal harvest and use in correc ... Full text Link to item Cite

Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia.

Journal article Nat Commun · August 30, 2016 Many metabolic liver disorders are refractory to drug therapy and require orthotopic liver transplantation. Here we demonstrate a new strategy, which we call metabolic pathway reprogramming, to treat hereditary tyrosinaemia type I in mice; rather than edit ... Full text Link to item Cite

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.

Journal article J Hepatol · August 2016 BACKGROUND & AIMS: Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model ... Full text Link to item Cite

In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides.

Journal article J Hepatol · April 2016 BACKGROUND & AIMS: Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis ... Full text Link to item Cite

Combinatorial RNA Interference Therapy Prevents Selection of Pre-existing HBV Variants in Human Liver Chimeric Mice.

Journal article Sci Rep · October 20, 2015 Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously iden ... Full text Link to item Cite

The camKK2/camKIV relay is an essential regulator of hepatic cancer.

Journal article Hepatology · August 2015 UNLABELLED: Hepatic cancer is one of the most lethal cancers worldwide. Here, we report that the expression of Ca(2+) /calmodulin-dependent protein kinase kinase 2 (CaMKK2) is significantly up-regulated in hepatocellular carcinoma (HCC) and negatively corr ... Full text Link to item Cite

Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model.

Journal article Nat Commun · June 17, 2015 Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused ... Full text Link to item Cite

KDR identifies a conserved human and murine hepatic progenitor and instructs early liver development.

Journal article Cell Stem Cell · June 6, 2013 Understanding the fetal hepatic niche is essential for optimizing the generation of functional hepatocyte-like cells (hepatic cells) from human embryonic stem cells (hESCs). Here, we show that KDR (VEGFR2/FLK-1), previously assumed to be mostly restricted ... Full text Link to item Cite

A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity.

Journal article Curr Biol · January 11, 2011 Human embryonic stem (hES) cells show an atypical cell-cycle regulation characterized by a high proliferation rate and a short G1 phase. In fact, a shortened G1 phase might protect ES cells from external signals inducing differentiation, as shown for certa ... Full text Link to item Cite

Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment.

Journal article J Clin Invest · March 2010 A paucity of versatile small animal models of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has been an impediment to both furthering understanding of virus biology and testing antiviral therapies. We recently described a regulatable system ... Full text Link to item Cite

Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model.

Journal article Proc Natl Acad Sci U S A · December 18, 2007 We report the successful transplantation of human hepatocytes in immunodeficient, fumarylacetoacetate hydrolase-deficient (fah(-/-)) mice. Engraftment occurs over the entire liver acinus upon transplantation. A few weeks after transplantation, increasing c ... Full text Link to item Cite

Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat--a feasibility study.

Journal article Biometals · February 2005 Copper is an essential trace element. However, excess copper can lead to oxidation of biomolecules and cell damage and copper levels must be carefully controlled. While copper homeostasis has been studied extensively at the cellular level, short-term body ... Full text Link to item Cite

Tetrathiomolybdate inhibition of the Enterococcus hirae CopB copper ATPase.

Journal article FEBS Lett · November 2, 2001 Tetrathiomolybdate (TTM) avidly interacts with copper and has recently been employed to reduce excess copper in patients with Wilson disease. We found that TTM inhibits the purified Enterococcus hirae CopB copper ATPase with an IC(50) of 34 nM. Dithiomolyb ... Full text Link to item Cite

Interaction of the CopZ copper chaperone with the CopA copper ATPase of Enterococcus hirae assessed by surface plasmon resonance.

Journal article Biochem Biophys Res Commun · October 19, 2001 Intracellular copper routing in Enterococcus hirae can be accomplished by the CopZ metallochaperone. Using surface plasmon resonance analysis, we show here that CopZ interacts with the CopA copper ATPase. The binding affinity of CopZ for CopA was increased ... Full text Link to item Cite

Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: effect of Menkes/Wilson disease mutation homologues.

Journal article Biochem J · July 1, 2001 The Enterococcus hirae CopB ATPase (EC 3.6.1.3) confers copper resistance to the organism by expelling excess copper. Two related human ATPase genes, ATP7A (EC 3.6.1.36) and ATP7B (EC 3.6.1.36), have been cloned as the loci of mutations causing Menkes and ... Full text Link to item Cite

Expression of the human Menkes ATPase in Xenopus laevis oocytes.

Journal article Biol Chem · April 2001 Menkes disease is an X-linked disorder of copper metabolism that is usually fatal. The affected gene has recently been cloned and encodes one of the two human copper ATPases. If the Menkes ATPase is defective, copper is trapped in the intestinal mucosa, le ... Full text Link to item Cite

Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy.

Journal article J Hepatol · August 2000 BACKGROUND/AIMS: Epidermal growth factor, a potent mitogen for hepatocytes and cholangiocytes, is thought to act as an immediate-early gene after partial hepatectomy. Since regeneration is impaired in cirrhosis, we explored the expression of epidermal grow ... Full text Link to item Cite

[How (deficient) copper causes illness].

Journal article Schweiz Med Wochenschr · August 4, 1998 Copper is an essential cofactor in all cells. However, it remains largely unknown how cells deal with this element, which is essential yet toxic. Through the study of microbial model systems on the one hand, and the investigation of inherited diseases in c ... Link to item Cite