BALB/c-hCRBN Mice

Catalog Number: C001724

Strain Name: BALB/cAnCya-Crbnem1(hCRBN)/Cya

Genetic Background: BALB/cAnCya

 

Strain Description

The CRBN gene, located on chromosome 3, exhibits broad expression across diverse tissues, including the brain, kidney, muscle, and immune cell populations such as monocytes, macrophages, dendritic cells, and B lymphocytes [1]. This gene encodes cereblon, a protein that functions as a key substrate receptor within the CRL4-CRBN E3 ubiquitin ligase complex. This complex mediates the ubiquitination and subsequent proteasomal degradation of specific target proteins, thereby regulating crucial cellular processes encompassing protein homeostasis, ion transport, and AMPK signaling [1-2]. Notably, mutations in CRBN are implicated in autosomal recessive nonsyndromic intellectual disability [2]. Furthermore, Cereblon protein serves as a primary molecular target for targeted protein degradation (TBD) therapy by specifically modulating the enzymatic activity of the CRL4-CRBN complex and altering its substrate recognition properties, thereby enabling the selective degradation of specific transcription factors. This molecular mechanism has emerged as a critical theoretical foundation for the clinical treatment of malignant hematological malignancies such as multiple myeloma, leading to the development of diverse therapeutic modalities including molecular glues and proteolysis targeting chimeras (PROTACs) [3-5].

BALB/c-hCRBN mice are humanized models generated by gene editing technology, in which the exon 2 to partial intron 2 of the mouse Crbn gene was replaced in situ with the Exon 2~11 of the coding sequence (CDS) of human CRBN gene. This model can be used to study the pathological mechanisms and therapeutic methods of autosomal recessive nonsyndromic intellectual disability and multiple myeloma and other hematological cancers, as well as the screening, development, and preclinical efficacy and safety evaluation of CRBN-based targeted protein degradation (TBD) therapies.

 

Strain Strategy


Figure 1. Gene editing strategy of BALB/c-hCRBN mice. The exon 2 to partial intron 2 of mouse Crbn will be replaced with “Exon 2~11 of Human CRBN CDS-BGH pA” cassette.

 

Application

  • Screening, development, and preclinical efficacy evaluation of CRBN-based targeted protein degradation (TBD) therapies;
  • Study of pathological mechanisms and therapeutic methods for autosomal recessive nonsyndromic intellectual disability;
  • Study of pathological mechanisms and therapeutic methods for multiple myeloma and other hematological cancers.

 

References
[1]Barankiewicz J, Salomon-Perzyński A, Misiewicz-Krzemińska I, Lech-Marańda E. CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma. Cancers (Basel). 2022 Sep 16;14(18):4492.
[2]Zhou L, Xu G. The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer and Neurological Diseases. J Mol Biol. 2022 Mar 15;434(5):167457.
[3]An J, Zhang X. Crbn-based molecular Glues: Breakthroughs and perspectives. Bioorg Med Chem. 2024 Apr 15;104:117683.
[4]Yamamoto J, Ito T, Yamaguchi Y, Handa H. Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders. Chem Soc Rev. 2022 Aug 1;51(15):6234-6250.
[5]Thapa R, Bhat AA, Gupta G, Renuka Jyothi S, Kaur I, Kumar S, Sharma N, Prasad GVS, Pramanik A, Ali H. CRBN-PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications. Chem Biol Drug Des. 2024 Nov;104(5):e70009.