Alexander's Disease (AxD), also known as fibrous protein malnutrition or giant brain infantile white matter malnutrition, is a disorder primarily affecting infants and children. It is characterized by motor and cognitive impairments, as well as epileptic seizures. The condition is inherited in an autosomal dominant manner. Astrocytes, a critical component of the central nervous system (CNS), play a key role in regulating ion balance, neurotransmitter uptake and metabolism, synaptic formation and stability, and the blood-brain barrier function ^[1]. GFAP (Glial Fibrillary Acidic Protein) is a member of the intermediate filament family. The network formed by GFAP provides support and strength to cells. During the development of astrocytes, GFAP protein molecules bind together to form the major intermediate filaments, which are essential components of their cellular cytoskeleton ^[2]. Gain-of-function (GOF) mutations in the GFAP gene lead to Alexander's Disease (AxD).

The GFAP gene encodes glial fibrillary acidic protein. It plays a role in intracellular cytoskeletal reorganization, cell adhesion, maintenance of brain myelin sheath formation, and neuronal structure. Under normal conditions, GFAP protein forms homodimers and serves its function. However, mutations in the GFAP gene lead to protein misaccumulation, resulting in the formation of abnormal inclusions known as Rosenthal fibers. These fibers can cause damage to the brain’s white matter (myelin sheath) in patients with AxD. Research indicates that the downregulation of GFAP can reduce the severity of traumatic brain injury, making GFAP a potential drug target for such injuries ^[3].

Several GFAP-targeting therapeutic drugs are currently undergoing clinical or preclinical studies, especially small molecule drugs and ASO drugs targeting GFAP, which are indicated for Alexander's disease and traumatic brain injury. Since most ASO drugs and gene therapies act on the human GFAP genes, considering the differences between animals and humans in genes, humanizing the rat gene will help promote the further clinical translation of therapies targeting GFAP. This strain is a rat Gfap gene humanized model and can be used for research on neurological diseases such as Alexander's disease and traumatic brain injury. The homozygotes 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 and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.