Humanized Knockin Mouse Models

For academic research: Phenocopy a human disease to decipher causes and molecular mechanisms Create a mouse model that is tolerant of human antigen to study human peptide functions

For bio-pharmaceutical research & development: Phenocopy human diseases for drug development and safety studies Provides a model to study efficacy when endogenous mouse target shows low affinity to xenobiotics or biologics Create a mouse model tolerant of human antigen for antibody or antibody drug conjugate (ADC) testing Human cytokine expression to improve human immune system engraftment

+	Physiological expression patterns due to the murine promoter and regulatory elements Murine gene is inactivated; no hybrid sequences (like, e.g., in transgenic animals) Combination with access to Knockout model for specificity studies

-	Risk of differential expression in mouse vs. human, due to differences in protein regulation Low conservation between human/mouse protein => risk of hypomorphism up to protein Knockout →  Limitation can be bypassed by using chimeric molecules to improve functionality in mouse cells

Case 1 | Study of a human-specific receptor

Schwarz F, et al. Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen. EMBO J. 2017.

E. coli K1 is a human-specific pathogen that appears to exploit a receptor Siglec-11 expressed only in the human brain.
Mice do not have paired Siglec receptors.

Model: Mice expressing a chimeric, human-type paired Siglec receptor E16.

Aim: To demonstrate that activating Siglecs confer better protection against bacterial infection in vivo.

Results: Siglec-E16 was able to produce protective inflammatory responses to bacterial infection.

 

Figure 1. Schematic representation of Siglec-E and Siglec-E16 receptors.

The parts of Siglec-E16 derived from mouse Siglec-E or human Siglec-16 are drawn in gray and black, respectively.

 

 

Figure 2. Activating Siglecs confer protection against E. coli K1 challenge.

A) Decreased E. coli survival in blood from E16/E16 mice, 1 hour after infection.

B) Less recovered bacteria from blood, spleen, and liver from E16/E16 mice.

C) Increased cytokine levels in serum from E16/E16 mice, 1 hour after bacterial challenge.

 

Case 2 | Biomarker identification in a rare disease ALD model

van de Beek MC, et al. C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man. PLoS One. 2016.

X-linked adrenoleukodystrophy, ALD, is a progressive neurodegenerative disease, and a result of very-long-chain fatty acid (VLCFA) buildup caused by relevant enzymes not functioning properly (mutations in Abcd1).

Model: Abcd1 Knockout overexpressing human Evolv1, an essential enzyme in the elongation of VLCFA (C22:0 to C26:0).

Aim: To develop an ALD model with increased VLCFA (>C22) levels in the central nervous system for the identification of new biomarkers for ALD.

Results: The VLCFA C26:0-Carnitine is a new biomarker for ALD that reflects elevated VLCFA levels present in the central nervous system of mice and humans.

 

Figure 1. C26:0-carnitine is highly elevated in central nervous tissue.

C26:0-carnitine levels in brain and spinal cord from wildtype (n=6), Abcd1^y/- knockout (n=6) and Abcd1^y/-;Cnp-ELOVL1^+/- (n=6) mice.

 

Figure 2. C26:0-carnitine is highly elevated in mouse and human bloodspots.

Left) Bloodspot C26:0-carnitine in wildtype (n=8), Abcd1^y/- knockout (n=10) and Abcd1^y/-;Cnp-ELOVL1^+/- (n=6) mice.

Right) Bloodspot C26:0-carnitine in controls (n=23) and ALD patients (n=10).

 

Case 3 | Functional validation of an antibody against GPCR

Butcher AJ, et al. An Antibody Biosensor Establishes the Activation of the M1 Muscarinic Acetylcholine Receptor during Learning and Memory. J Biol Chem. 2016.

Establishing the in vivo activation status of G protein-coupled receptors (GPCRs) would not only indicate physiological roles of GPCRs but would also aid drug discovery by establishing drug-receptor engagement.

Model: Mice expressing a humanized, mutated form of the GPCR M1mAChR.

Aim: To develop a phospho-specific antibody-based biosensor to detect activation of the M1 muscarinic acetylcholine receptor in vitro and in vivo.

Results: Phosphorylation sites can be used to probe the activation status of GPCRs during physiological responses and on drug treatment.

Figure 1. Detection of phosphorylation of M1 DREADD receptor in the hippocampus following receptor activation with a selective agonist.

A) Illustration of M1 DREADD receptor. Two point mutations were introduced into the human M1 mAChR, abolishing the activation by ACh, but instead the receptor could be activated by the drug CNO.

 

 

B) Fixed sections from M1 mAChRKO mice (M1-KO) or M1 DREADD KI mice treated with vehicle or CNO were co-stained with anti-HA (green) and anti phospho-specific antibodies (red).

The arrows indicate two neurons, where the staining for the receptor and the phosphorylated receptor occur in the same neuron.

The areas marked by the white box are magnified in the lower panels.

 

Case 4 | Human disease model for acute myeloid leukemia (AML)

Sportoletti P, et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood. 2013.

The NPM1 mutation is a frequent genetic alteration in acute myeloid leukemia (AML). Despite progress in the clinical and biological characterization of NPM1-mutated AML, the role of NPM1 mutation in leukemogenesis in vivo has not been fully elucidated.

Model: Mice that conditionally express the most common human NPM1 mutation (type A) in the hematopoietic compartment.

Aim: To develop an AML model to identify the role of NPM1 in leukemogenesis.

Results: The NPM1 mutant affects megakaryocytic development in mice and mimics some features of human NPM1-mutated AML.

Figure 1. Immature megakariocytes were increased 2-fold in heterozygous (Npm1-TCTG/WT;Cre1) and 4-fold in homozygous (Npm1-TCTG/TCTG;Cre1) mutant mice. A) Flow cytometric analysis of single-cell suspension of BM.

B) Quantification of CD411 megakaryocytic cells in the BM of age-matched mutant mice analyzed as in panel A.

Figure 2. Perturbation in megakaryocyte growth shown in in vitro colony-forming assays. A) Npm1-TCTG/WT;Cre1 BM cells formed significantly more megakaryocytic colonies (CFU-MK) than Cre2 control in semisolid media (34.00 6 5.367 vs 9.0 6 1.265 CFUMK/ 105BMcells; n56, P,.01). B) CFU-MK sizes were similar.

Chiahsuan Chin, Ranjithkumar Ravichandran, Kristina Sanborn, Timothy Fleming, Stephen B Wheatcroft, Mark T Kearney, Sofya Tokman, Rajat Walia, Michael A Smith, David J Flint, Thalachallour Mohanakumar, Ross M Bremner, Angara Sureshbabu.
Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis.
Cell Rep Med. 2023 Feb 9

Christoph Hudemann, Yvonne Exner, Robert Pollmann, Karina Schneider, Anna Zakrzewicz, Simon Feldhoff, Thomas Schmidt, Volker Spindler, David Rafei-Shamsabadi, Frauke Völlner, Jens Waschke, Ritva Tikkanen, Michael Hertl, Rüdiger Eming.
IgG against the Membrane-Proximal Portion of the Desmoglein 3 Ectodomain Induces Loss of Keratinocyte Adhesion, a Hallmark in Pemphigus Vulgaris.
J Invest Dermatol. 2023 Feb

Karianne Fjeld, Anny Gravdal, Ranveig S Brekke, Jahedul Alam, Steven J Wilhelm, Khadija El Jellas, Helene N Pettersen, Jianguo Lin, Marie H Solheim, Solrun J Steine, Bente B Johansson, Pål R Njølstad, Caroline S Verbeke, Xunjun Xiao, Mark E Lowe, Anders Molven.
The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice.
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Frédéric Adam, Alexandre Kauskot, Lamia Lamrani, Jean Solarz, Christelle Soukaseum, Christelle Repérant, Cécile V Denis, Hana Raslova, Jean-Philippe Rosa, Marijke Bryckaert.
A gain-of-function filamin A mutation in mouse platelets induces thrombus instability.
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Julia Leschik, Antonietta Gentile, Cigdem Cicek, Sophie Péron, Margaryta Tevosian, Annika Beer, Konstantin Radyushkin, Anna Bludau, Karl Ebner, Inga Neumann, Nicolas Singewald, Benedikt Berninger, Volkmar Lessmann, Beat Lutz.
Brain-derived neurotrophic factor expression in serotonergic neurons improves stress resilience and promotes adult hippocampal neurogenesis
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A humanized β 2 integrin knockin mouse reveals localized intra- and extravascular neutrophil integrin activation in vivo.
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Li-Chiung Lin, Tezz Quon, Susanna Engberg, Amanda E Mackenzie, Andrew B Tobin, Graeme Milligan
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Flavia Amadeu de Oliveira, Sonoko Narisawa, Massimo Bottini, José Luis Millán.
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Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse.
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Beyer S, Schwalm S, Pfeilschifter J, Huwiler A.
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PLoS One. 2017 Oct 12.

Schwarz F, Landig CS, Siddiqui S, Secundino I, Olson J, Varki N, Nizet V, Varki A.
Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen.
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C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man.
PLoS One. 2016 Apr 28.

Butcher AJ, Bradley SJ, Prihandoko R, Brooke SM, Mogg A, Bourgognon JM, Macedo-Hatch T, Edwards JM, Bottrill AR, Challiss RA, Broad LM, Felder CC, Tobin AB.
An antibody biosensor establishes the activation of the M1 muscarinic acetylcholine receptor during learning and memory.
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Blood. 2013 Apr 25.

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