What is Transthyretin Amyloidosis?

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

TTR is a 55 kDa protein composed of 127 amino acids, primarily found in plasma and cerebrospinal fluid (CSF), responsible for transporting thyroxine (T4) and retinol-binding protein 4 (RBP4). The misfolding of TTR leads to its deposition in tissues, forming amyloid fibrils that subsequently cause dysfunction in various organs. ATTR is primarily classified into two types: Familial Amyloidotic Polyneuropathy (FAP) and Transthyretin Amyloid Cardiomyopathy (ATTR-CM).

FAP primarily affects the nervous system, causing gradual degeneration of sensory neurons, leading to symptoms such as pain and paresthesia. ATTR-CM leads to myocardial stiffness and heart failure. The global prevalence of hereditary ATTR (hATTR) is estimated at approximately 10,000 to 40,000 cases, while ATTR-CM affects an estimated 300,000 to 500,000 individuals.

Pathogenesis

The process of TTR amyloidogenesis involves the dissociation of the TTR tetramer, partial unfolding of monomers, formation of non-fibrillar aggregates, protofibrils, and finally mature amyloid fibrils. Mutations in TTR are the primary cause of ATTR. These mutations reduce the stability of the TTR protein, making it more prone to misfolding and deposition. Over 120 different TTR gene mutations associated with ATTR have been identified.

(Image: PubMed. Pathogenesis and Clinical Manifestations of ATTR Amyloidosis)

Gene Therapy
 

(I) RNA Interference (RNAi)
 

RNAi is a technique that uses small interfering RNA (siRNA) to suppress the expression of a specific gene. In ATTR treatment, RNAi is used to lower TTR protein expression. For example, patisiran is an siRNA drug targeting TTR mRNA. Delivered via intravenous infusion, it significantly reduces serum TTR protein levels.
 

(II) Antisense Oligonucleotides (ASOs)
 

ASOs are single-stranded DNA or RNA molecules that bind to mRNA and prevent its translation. Inotersen is an ASO drug targeting TTR mRNA. Administered via subcutaneous injection, it reduces serum TTR protein levels and slows disease progression.
 

(III) Gene Editing
 

Aims to treat ATTR by precisely modifying the mutation site in the genome. For instance, research teams have performed gene editing in mouse livers, successfully reducing TTR protein levels. This approach has the potential for single-dose treatment and permanent TTR reduction but remains in the research stage. Companies like Intellia Therapeutics and Regeneron Pharmaceuticals are investigating CRISPR-based therapies like NTLA-2001 for ATTR.
 

Mouse Models
 

● ATTR V30M Mice: These mice express the human V30M TTR mutant. Human TTR protein is detectable in their serum, but they lack amyloid deposition in the peripheral or autonomic nervous systems. Mild TTR amyloid deposition is found in the kidneys, gastrointestinal tract (GIT), and cardiovascular organs of these mice.

● TTR A97S (hTTRA97S) Mice: Generated by knocking the human TTR A97S mutant gene into the mouse Ttrlocus. This mutation is associated with late-onset presentation in patients characterized by axonal degeneration. Congo-red-positive amyloid deposits are detected in the perineurium of the sciatic nerve, distal convoluted tubules of the kidneys, 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, lower nerve fiber density, and reduced sensory perception.

● Dual-Humanized TTR/Rbp4 Mouse Model: Generated by humanizing the TTR and Rbp4 gene loci, this model more accurately simulates the human ATTR pathological process. Studies show that dual-humanized mice exhibit lower serum levels of hTTR and hRbp4 but demonstrate more significant amyloid deposition in the sciatic nerve.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various ATTR mouse models according to client needs, such as ATTR V30M mice, TTR A97S mice, and dual-humanized TTR/Rbp4 mouse models. We welcome inquiries!
 

References:

[1] Merck Manual Professional Edition. Amyloidosis. Endocrine and Metabolic Disorders: Amyloidosis.

[2] Ibrahim RB, Liu YT, Yeh SY, Tsai JW. Contributions of Animal Models to the Mechanisms and Therapies of Transthyretin Amyloidosis. Front Physiol. 2019 Apr 2;10:338. doi: 10.3389/fphys.2019.00338. PMID: 31001136; PMCID: PMC6454033.

[3] Li X, Lyu Y, Shen J, Mu Y, Qiang L, Liu L, Araki K, Imbimbo BP, Yamamura KI, Jin S, Li Z. Amyloid deposition in a mouse model humanized at the transthyretin and retinol-binding protein 4 loci. Lab Invest. 2018 Apr;98(4):512-524. doi: 10.1038/s41374-017-0019-y. PMID: 29330472.

[4] Advances in Clinical Medicine, 2024, 14(1), 476-487.

[5] Intellia and Regeneron Announce Updated Phase 1 Data Demonstrating a Single Dose of NTLA-2001, an Investigational CRISPR Therapy for Transthyretin (ATTR) Amyloidosis, Resulted in Rapid, Deep and Sustained Reduction in Disease-Causing Protein.

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