B6-hSMN2 (SMA) Mouse

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the progressive loss of anterior horn motor neurons in the spinal cord, leading to muscle weakness and atrophy. This can affect the muscles that control breathing, crawling, walking, head and neck control, and swallowing, increasing the risk of pneumonia and respiratory infections in patients. SMA is the most common fatal neurogenetic disease in infancy, with an incidence rate of 1/6,000 to 1/10,000.

SMA is caused by mutations in the SMN1 gene, which encodes a protein essential for motor neuron survival. The human genome also contains the SMN2 gene, which is highly homologous to SMN1 but differs in splicing patterns. A c.840C>T mutation in the splicing enhancer of exon 7 of SMN2 causes it to produce mostly truncated mRNA, which encodes a non-functional protein. Only a small portion of SMN2 mRNA, approximately 10%~15%, is spliced into full-length mRNA, which encodes functional protein ^[1]. Approximately 95% of SMA patients carry either the homozygous SMN1 exon 7 deletion mutation or the homozygous mutation that converts SMN1 to SMN2, and the inability of SMN2 expression to compensate for the deletion of SMN proteins leads to disease ^[2]. Mice are the most common preclinical experimental subjects for SMA, but they only have the Smn1 gene, and the deletion of both Smn1 alleles leads to lethality. Therefore, it is crucial to develop mouse models that can simulate human SMA pathogenesis and progression. Current therapies for SMA aim to supplement SMN1 genes or selectively regulate SMN2 splicing. Targeted therapy for SMN2 changes its splicing pattern to increase the expression of full-length SMN protein ^[3]. The application of fully humanized animal models can help promote the further translation of potential SMA-related therapies into clinical trials.

This strain is a humanized SMN2 gene model of spinal muscular atrophy (SMA). The endogenous Smn1 gene in mice was replaced with the human SMN2 gene fragment to simulate the pathogenesis of SMA patients in mice. However, since the SMN2 gene mainly produces the SMNΔ7 protein, which lacks exon 7, the humanized SMN2 gene cannot fully compensate for the abnormalities caused by the loss of the Smn1 gene, resulting in an SMA-like phenotype in the model. Due to the correlation between SMA subtypes and SMN2 copy numbers, this model can be mated with Rosa26-hSMN2 mice, which have SMN2 genes inserted in chromosome 6, to increase the copy number of SMN2 in mice and improve the survival period of the model. This can simulate different SMA subtypes, which can be used for more relevant pathogenic mechanisms and preclinical studies of drugs.