huUSH2A(E10-15) Mouse

Usher syndrome (USH), also referred to as hereditary deafness-retinitis pigmentosa syndrome or retinitis pigmentosa-neurosensory deafness syndrome, is an autosomal recessive disorder marked by genetic heterogeneity. The primary clinical manifestations include congenital sensorineural hearing loss, progressive retinitis pigmentosa (RP), and visual impairment. USH is the leading disorder resulting in deafness and blindness, with an estimated prevalence ranging from 1 in 5,000 to 1 in 16,000 individuals. USH is classified into three subtypes—USH1, USH2, and USH3—based on the age of onset and effects on hearing and vestibular function. Patients with USH1 present with profound congenital deafness and vestibular dysfunction, typically developing RP before adulthood. USH2 is characterized by moderate to severe hearing loss without vestibular dysfunction, with RP symptoms manifesting later in adulthood. USH3 patients are born with normal hearing, which progressively declines alongside the onset of RP. USH1 is the most severe form, while USH2 is the most prevalent, accounting for 40%–50% of cases. However, underdiagnosis and the gradual progression of the disease suggest that the true prevalence of USH2 may be underestimated. The USH2A gene is the primary causative gene for USH2, with 75%–90% of USH2 cases linked to mutations in this gene ^[1].

The USH2A gene encodes Usherin, a protein featuring laminin EGF-like, pentraxin, and fibronectin type III domains, predominantly expressed in the basement membrane of the inner ear and retina. Usherin plays a critical role in developing hair cells in the inner ear, auditory signal transduction, and the maintenance of adhesion via interactions with fibronectin in the retinal basement membrane. Mutations in the USH2A gene disrupt the normal development and function of hair cells, impair fibronectin assembly, and compromise the adhesive properties of the retinal basement membrane, leading to hearing loss and RP symptoms. Currently, there are no effective therapies for Usher syndrome. Ongoing research focuses on elucidating the genetic mechanisms underlying the disorder and developing gene-based therapeutic strategies. While gene therapy remains preclinical, promising advances have been made with antisense oligonucleotides (ASO) and CRISPR-based gene-editing technologies. QR-421a, an RNA-based oligonucleotide therapy developed by ProQR Therapeutics, targets exon 13 mutations in the USH2A gene associated with USH and non-syndromic RP. This therapeutic approach aims to restore Usherin expression by correcting exon 13 deletions through exon skipping.

Given the focus of ASO and CRISPR therapies on the human USH2A gene, developing humanized mouse models is critical to advancing gene therapies toward clinical applications. Exon 13 of the USH2A gene harbors a hotspot for pathogenic mutations associated with USH, including two common mutations, c.2299delG and c.2276G>T, which are the subject of several therapeutic investigations ^{[2-4, 6]}. The huUSH2A(E10-15) mouse model, in which the corresponding mouse Ush2a gene sequence was replaced with human USH2A exons 10 to 15 and their flanking regions, provides a valuable tool for studying USH pathogenesis and evaluating preclinical treatments. Homozygous huUSH2A(E10-15) mice are viable and fertile, making them suitable for drug evaluation and disease modeling. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.