What is Transthyretin Amyloidosis?​​

 

Transthyretin Amyloidosis (ATTR) is a rare systemic disorder caused by the deposition of amyloid fibrils derived from misfolded transthyretin (TTR) protein.

 

TTR is a 55 kDa protein composed of 127 amino acids, primarily found in plasma and cerebrospinal fluid (CSF), where it functions as a transport protein for thyroxine (T4) and retinol-binding protein 4 (RBP4). Misfolding of TTR leads to its accumulation in tissues, forming amyloid fibrils that subsequently cause dysfunction in multiple organs. ATTR is mainly classified into two types: Familial Amyloidotic Polyneuropathy (FAP) and Transthyretin Amyloid Cardiomyopathy (ATTR-CM).

 

FAP primarily affects the peripheral and autonomic nervous systems, leading to progressive degeneration of sensory neurons and symptoms such as pain and paresthesia. ATTR-CM results in myocardial stiffening and heart failure. The global prevalence of hereditary ATTR (hATTR) is estimated at 10,000–40,000 cases, while ATTR-CM affects approximately 300,000–500,000 individuals.

 

​Pathogenesis​

 

The process of TTR amyloidogenesis involves dissociation of the TTR tetramer, partial unfolding of monomers, formation of non-fibrillar aggregates, protofibrils, and finally mature amyloid fibrils. Mutations in the TTR gene are the primary cause of ATTR, as they reduce the stability of the TTR protein, promoting misfolding and deposition. To date, more than 120 TTR gene mutations have been associated with ATTR.

 

​Gene Therapy Approaches​

 

​​(I) RNA Interference (RNAi)​​

 

RNAi is a technique that uses small interfering RNAs (siRNAs) to inhibit the expression of specific genes. In ATTR treatment, RNAi is employed to reduce TTR protein production. For example, patisiran—an siRNA drug targeting TTR mRNA—is delivered via intravenous infusion to the liver and has been shown to significantly reduce serum TTR levels.

 

​​(II) Antisense Oligonucleotides (ASOs)​​

 

ASOs are single-stranded DNA or RNA molecules that bind to mRNA and prevent its translation. Inotersen, an ASO drug targeting TTR mRNA, is administered subcutaneously and reduces serum TTR levels, slowing disease progression.

 

​​(III) Gene Editing​

 

This approach aims to correct the underlying genetic mutation in the TTR gene. For instance, studies in mouse models have demonstrated successful reduction of TTR protein levels following gene editing in the liver. While this strategy holds promise for a one-time, permanent reduction of TTR levels, it remains in the research stage.

 

​Mouse Models​

 

​ATTR V30M Mouse: This model expresses human TTR protein detectable in serum but does not develop amyloid deposits in the nervous or autonomic systems under standard conditions. Mild TTR amyloid deposits have been observed in the kidneys, gastrointestinal tract, and cardiovascular organs of these mice.

 

​TTR A97S (hTTRA97S) Mouse: This model carries a humanized TTR gene with the A97S mutation, mimicking the late-onset phenotype characterized by axonal degeneration seen in patients. Congo red-positive amyloid deposits are detected in the epineurium of the sciatic nerve, distal convoluted tubules of the kidney, and other organs in aged hTTRA97S mice (>2 years old), but not in younger adults (8–56 weeks). Aged hTTRA97S mice also exhibit hypersensitivity to mechanical stimuli, reduced nerve fiber density, and impaired sensory function.

 

​Double Humanized TTR/RBP4 Mouse Model: By humanizing the TTR and RBP4 gene loci, this model more accurately recapitulates the human ATTR pathological process. Studies show that while these mice exhibit lower serum levels of human TTR (hTTR) and human RBP4 (hRBP4), they develop more prominent amyloid deposits in the sciatic nerve.

 

​MingCeler Biotech Supports Gene Therapy Development​

 

Gene therapy offers hope for rare diseases, but its development and validation rely heavily on robust animal models. Leveraging its proprietary TurboMice™ platform, Mingxun Biotech has developed a range of rare disease mouse models. The TurboMice™ technology addresses key challenges such as prolonged modeling cycles and low success rates for complex models, enabling precise editing at virtually any target genomic locus. It allows for the generation of fully homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

 

MingCeler Biotech provides custom services for developing various ATTR mouse models, including ATTR V30M, TTR A97S, and double humanized TTR/RBP4 models. We welcome inquiries to support your specific research needs.