The Scope and Limitations of In Vivo and In Silico Models of Cardiac Amyloidosis

Abstract

Amyloidosis is a systemic disease, leading to the disfunction of many organs. There are several clinical and morphological forms of amyloidosis based on the organ-specific nature of amyloid fibril deposition, which is found in the heart, brain, kidneys, spleen, liver, pancreas, thyroid glands, bone marrow and intestines. The nature of organ damage correlates with the types of amyloid fibrils. Thus, damage to the tissues of the heart and kidneys are the most significant factors affecting mortality. The complexity of drug molecule discovery against amyloidosis is connected with the fact that more than 30 proteins are involved in fibril formation. The fact that only two small molecules, namely diflunisal and tafamidis, are clinically used nowadays underlines the complexity in this field of research. The mechanism of action for both drugs include the stabilization of the tetrameric form of transthyretin. The crucial approach for the discovery of drug molecules against cardiac amyloidosis requires the use of predictive models. The main restrictions of most developed in vivo models, however, are related to their reproducibility and cost. Therefore, an in silico approach may be a relatively effective procedure to minimize time and difficulty during the drug discovery process. In this paper, we collected key information which highlights the scope and limitations of the development of an in silico approach.

Keywords

• cardiac amyloidosis
• amyloid fibrils
• models
• in vitro
• in vivo
• in silico