H11-Alb-hTTR*V50M Mouse

Transthyretin amyloidosis (ATTR) is a protein misfolding disorder caused by the abnormal accumulation of misfolded transthyretin (TTR) protein in organs and tissues throughout the body. It primarily affects the peripheral nervous system and the heart ^[1]. Hereditary ATTR (ATTRv) results from genetic mutations in the TTR gene. The TTR gene encodes transthyretin, also known as prealbumin. This protein is primarily synthesized in the liver, with a smaller amount produced in the choroid plexus of the brain or the light-sensitive tissue in the eye (such as the retina). TTR functions as a transport protein and normally exists in the peripheral blood as a homotetramer, participating in the transport of thyroid hormones and retinol-binding protein.

Over 130 TTR variants have been identified, among which the Val50Met (V50M) mutation, also known as c.148G>A and V30M, is the most common in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) ^[2-6]. Most ATTRv patients with the Val50Met mutation, if left untreated, will progress to complete disability or even death within 10 to 15 years after diagnosis. Their neurological symptoms may also be accompanied by gastrointestinal dysfunction, cardiomyopathy, renal disease, or ocular deposits ^[7].

The primary treatment for ATTR mainly involves inhibiting the production of mutant TTR gene mRNA or stabilizing the structure of TTR protein tetramers. In the current stage of research targeting TTR, several innovative therapeutic pipelines have emerged, including ASO (antisense oligonucleotide) drugs, siRNA drugs, and CRISPR-based gene therapies. Inotersen Sodium, developed by the leading nucleic acid drug company Ionis, specifically targets the conservative sequence in the 3’ untranslated region of TTR mRNA, inducing mRNA degradation to reduce TTR synthesis in liver cells. It is the first ASO drug approved for this disease ^[8]. Given that most ASO, siRNA, and CRISPR-based therapies target the human TTR gene, humanizing mouse genes can accelerate the TTR-targeted treatments into clinical stages.

This strain is a Ttr humanized model and can be used for research on ATTRv-PN. A human TTR gene fragment carrying the V50M mutation, driven by the mouse Alb promoter (liver-specific promoter), is inserted at the H11 safe harbor. This modification does not affect the expression of the mouse Ttr gene. The homozygous H11-Alb-hTTR*V50M mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also provide customized services to meet experimental needs.