huFUS Mouse

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal progressive neurodegenerative disease. The disease is caused by the degeneration and death of motor neurons that control skeletal muscles in the central nervous system, leading to gradual muscle weakness and atrophy, and ultimately complete loss of voluntary movement control by the brain ^[1]. Unlike Alzheimer’s disease, ALS does not necessarily affect higher brain functions. On the contrary, late-stage patients can maintain clear thinking and retain memories, personality, and intelligence before the onset of the disease. The known ALS-causing genes include SOD1, ALS2, TARDBP, and FUS, among others.

FUS is a multifunctional DNA/RNA binding protein typically located in the cell nucleus and can shuttle between the nucleus and cytoplasm. FUS protein plays an important role in RNA transcription, splicing, and microRNA processing. Mutations in the FUS gene are closely related to frontotemporal lobar degeneration/dementia (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). More than 50 FUS gene mutations have been identified in familial and sporadic ALS patients, most of which are autosomal dominant and most of which affect the nuclear localization signal (NLS) of FUS protein ^[2]. ALS-FUS patients have a histopathological feature of FUS protein mislocalization to the cytoplasm and formation of FUS-positive inclusions in spinal motor neurons and glial cells. However, in current cases, only some patients exhibit FUS mislocalization, and changes in the nuclear function of FUS mutants can also cause ALS. Studies have found that FUS pathological mice can induce neurodegeneration without cytoplasmic pathology or obvious mislocalization, which strongly suggests that the nuclear toxic function of FUS mutants may be a potential pathogenic mechanism ^[2].

Most FUS-targeting drugs in development are gene therapies, including antisense oligonucleotides (ASOs). The ASO drug ION363 developed by Ionis Pharmaceuticals can effectively reduce abnormal expression of FUS in diseased mice ^[3]. Humanizing mouse genes, given the genetic differences between animals and humans, can accelerate the development of FUS-targeted gene therapy for clinical use. This strain is a mouse Fus gene humanized model and can be used for research on ALS. The homozygous huFUS mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain (e.g., FUS (p.R521C)) and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields related to ALS.