Familial Amyloidosis

Familial Amyloidosis is a rare disorder, part of a larger group called inherited systemic amyloidosis, that is characterized by a progressive loss of organ function, primarily the kidneys, due to the abnormal accumulation of proteins. Protheragen is dedicated to advancing therapeutic solutions for rare kidney diseases. Here, we present our comprehensive service offerings for familial amyloidosis.

Introduction to Familial Amyloidosis

Familial Amyloidosis is a particularly uncommon group within the spectrum of autosomally-dominant diseases, triggered by alterations to the underlying genes that code for amyloid associated proteins, which leads to the abnormal accumulation of misfolded fibrillary proteins. It is present as hereditary transthyretin (hATTR) or fibrinogen Aα-chain (AFib) amyloidosis with an estimated incidence of 1 in 100,000 individuals. It typically affects the kidneys, peripheral nervous system and the heart. About 40% of patients with hATTR and almost all patients with AFib exhibit renal involvement (proteinuria and a falling GFR) which usually leads to the ESRD in 5 to 10 years.

Pathogenesis of Familial Amyloidosis

The specific subsystems in the problem within the familial problem of Amyloidosis are based on the -inherent genetic peculiaritiest of the particular kind of polymers. These are to some extent too readily genetically engineered to misfold and form insoluble and aggregantly amrphous solutions which then somehow get to be deposited in the extracellular regions of many organs.

Fig.1 Familial amyloidosis gene defect on chromosome 18q. (Barreiros et al., 2015)

In the kidneys, amyloidosis which is an accumulation of amyloid, manifests in the kidneys with the accumulation of amyloid in the glomeruli and nephron tubules and is also seen in the blood vessels and interstitial of the kidneys too. There is an involvement of glomerulus, where the amyloidosis manifests in the glomerular mesangial and also in the capillary circulation. This accumulation disrupts the glomeruli and the filtration barrier. This damage results in the loss of selective filtration of the proteins, excessive loss of proteins is also termed as nephrotic syndrome. With progressive accumulation of amyloid, there is restriction and loss of normal tissue architecture, lead to inflammation and progressive scarring (fibrosis) causing decrease of renal function. Depending on the primary site of the amyloidosis, the patients may mainly present with nephrotic syndrome or with progressive renal failure. This leads to chronic renal failure; in my many cases renal failure is in the end stage (ESRD).

Therapeutics Development for Familial Amyloidosis

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen specializes in developing advanced disease models for familial amyloidosis and offers comprehensive preclinical therapeutic development services. We focus on elucidating the diverse genetic and protein misfolding impacts that lead to the multi-systemic manifestations of familial amyloidosis.

Therapeutic Development Platforms for Familial Amyloidosis

• Small Molecule Drug
• Cell Therapy
• Gene Therapy

• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein

Disease Models Development for Familial Amyloidosis

Protheragen offers innovative and comprehensive disease models to advance preclinical research into Familial Amyloidosis. Our platform integrates advanced cell-based models, sophisticated kidney organoids, and relevant animal models to effectively capture the protein misfolding and amyloid deposition that characterize familial amyloidosis, supporting extensive drug discovery and mechanism-based investigations focused on protein homeostasis and organ pathology.

Cell-based & Organoid Models

• TTR^V30M mutant hepatocytes
• Amyloid-macrophage phagocytosis co-cultures
• hATTR glomeruloids
• AFib fibrinogen aggregation organoids

Animal Models

• Human TTR^V30M transgenic mice
• FGA^E526V knock-in rats
• TTR knockout zebrafish
• Amyloid xenograft NSG mice
• Spontaneously Hypertensive Rats

Drug Pharmacokinetics & Safety Evaluation Services

In Vitro ADME Services

• Metabolic Stability Assay
• Plasma Protein Binding
• Renal Tubular Epithelial Cell Uptake & Efflux
• Drug-Transporter Interaction Profiling
• Cellular Permeability

In Vivo Pharmacokinetics Services

• Systemic Pharmacokinetics
• Kidney Tissue Distribution and Retention
• Renal Clearance and Excretion Studies
• Urinary Metabolite Profiling
• Blood-to-Plasma Ratio

Drug Safety Evaluation

• General Toxicology Evaluation
• Genetic Toxicology Evaluation
• Developmental and Reproductive Toxicity Evaluation

• Immunogenicity and Immunotoxicity Evaluation
• Local Toxicity Evaluation
• Phototoxicity Evaluation

• Tissue Cross-Reactivity Evaluation
• Safety Pharmacology Evaluation
• Toxicokinetic Evaluation

Protheragen's integrated preclinical development solutions are specifically designed for research affecting renal systems, such as Familial Amyloidosis. We specialize in comprehensive disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your therapeutic investigations from initial target validation to IND-enabling studies.

Contact us today to accelerate your Familial Amyloidosis research with end-to-end solutions.

References

1. Barreiros, A. P., et al. "Familial Amyloidosis: Great Progress for an Orphan Disease." J Hepatol 62.2 (2015): 483-5.
2. Tseng, W. H., et al. "Natural History and Survival Rate of Familial Amyloidosis with Polyneuropathy: A Nationwide Databank." Ann Clin Transl Neurol 10.5 (2023): 779-86.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.