B6-hTFRC/hDMD(E49-53) Mice

Catalog Number: C001595

Strain Name: C57BL/6NCya-Tfrctm1(hTFRC)Dmdtm3(hDMD Exon 49-53)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

 

Strain Description

The Transferrin receptor (TFRC) gene encodes Transferrin Receptor 1 (TFR1), a protein that is expressed at low levels in most normal cells but shows increased expression in highly proliferative cells, such as basal epidermal cells, intestinal epithelium, and certain activated immune cells. Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), also express this receptor at high levels [1]. TFR1 plays a critical role in maintaining iron metabolism and homeostasis by facilitating receptor-mediated endocytosis of iron-bound transferrin (Tf) via Tf cycling, thereby promoting iron uptake [2]. Cellular iron deficiency can lead to apoptosis, while cellular transformation requires substantial iron to sustain proliferation, with iron overload contributing to tumor progression. The high expression of TFR1 in many tumors makes it a potential tumor marker, offering a target for therapies to inhibit tumor growth and metastasis [1]. Moreover, TFR1 is implicated in anemia and iron metabolism disorders. Studies have shown that elevated TFR1 expression in cardiomyocytes is associated with exacerbated inflammation in myocarditis patients [3]. Various clinical drugs targeting TFR1 are currently under development, including antisense oligonucleotides (ASOs), antibody-drug conjugates (ADCs), and antibody-oligonucleotide conjugates, applicable to diseases such as cancer, anemia, and neurodegenerative disorders. Research indicates that enhancing antibody transport across the blood-brain barrier via TFR1, by forming specific bispecific antibodies with anti-β-amyloid antibodies, can improve therapeutic outcomes in Alzheimer's patients [4-5]. As research progresses, TFR1 is expected to become an effective clinical target for multiple diseases and a synergistic target for drug delivery across the blood-brain barrier (BBB).

Duchenne Muscular Dystrophy (DMD) is a severe, progressive, and disabling X-linked recessive genetic disorder characterized primarily by muscle atrophy. This disease leads to motor impairments, eventually requiring assisted ventilation, and often results in premature death. The primary cause of DMD is mutations in the DMD gene, which encodes the dystrophin protein. These mutations lead to a reduction or absence of dystrophin in muscle tissue, resulting in muscle atrophy and related complications [6]. The lack of dystrophin leads to the breakdown of the dystrophin-associated protein complex (DAPC) within the muscle membrane, disrupting the interaction between actin and the extracellular matrix, and making the muscles more susceptible to damage. This susceptibility results in the gradual loss of muscle tissue and function, potentially leading to cardiomyopathy [7]. Researchers have identified thousands of different DMD gene mutations in patients with DMD. Deletion mutations account for approximately 60%–70%, while duplication mutations account for 5%–15%. These mutations are primarily concentrated in hotspot regions of the DMD gene, specifically between exons 45-55 (47%) and exons 3-9 (7%) [6].

The B6-hTFRC/hDMD(E49-53) mouse model is a humanized model obtained by breeding B6-hTFRC(CDS) mice (Product No.: C001584) with B6-hDMD(E49-53) mice (Product No.: I001133). This model can be used for research on iron metabolism disorders, Duchenne muscular dystrophy (DMD), neurodegenerative diseases, and tumor development, aiding in the research of TFRC/DMD-targeted drugs.
 

Strain Strategy

  • Construction strategy for B6-hTFRC(CDS) mice: Partial coding region of mouse Tfrc exon 2 sequences was replaced with the TFRC chimera CDS-WPRE-BGH pA cassette. Gene-editing techniques were employed to knock out exons 10-13 (~3.9 kb) of the mouse Tfrc gene.



  • Construction strategy for B6-hDMD (E49-53) mice: The partial intron 48 (~5kb) to partial intron 53 (~5kb) of mouse Dmd was replaced with the partial intron 48 (~5kb) to partial intron 53 (~5kb) of human DMD.



Application

  • Research on iron metabolism disorders, Duchenne Muscular Dystrophy (DMD), neurodegenerative diseases, and tumor development;
  • Development, screening, and efficacy evaluation of TFRC/DMD-targeted therapies;
  • Research and evaluation of drug delivery across the blood-brain barrier (BBB).

 

References
[1]Candelaria PV, Leoh LS, Penichet ML, Daniels-Wells TR. Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents. Front Immunol. 2021 Mar 17;12:607692.
[2]Xu W, Barrientos T, Mao L, Rockman HA, Sauve AA, Andrews NC. Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep. 2015 Oct 20;13(3):533-545.
[3]Kobak KA, Franczuk P, Schubert J, Dzięgała M, Kasztura M, Tkaczyszyn M, Drozd M, Kosiorek A, Kiczak L, Bania J, Ponikowski P, Jankowska EA. Primary Human Cardiomyocytes and Cardiofibroblasts Treated with Sera from Myocarditis Patients Exhibit an Increased Iron Demand and Complex Changes in the Gene Expression. Cells. 2021 Apr 6;10(4):818.
[4]Bray, Natasha. "Transferrin'bispecific antibodies across the blood–brain barrier." Nature Reviews Drug Discovery 14.1 (2015): 14-15.
[5]Pardridge, William M. "Blood–brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody." Expert opinion on drug delivery 12.2 (2015): 207-222.
[6]Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021 Feb 18;7(1):13.
[7]Babbs A, Chatzopoulou M, Edwards B, Squire SE, Wilkinson IVL, Wynne GM, Russell AJ, Davies KE. From diagnosis to therapy in Duchenne muscular dystrophy. Biochem Soc Trans. 2020 Jun 30;48(3):813-821.