What are TTR inhibitors and how do they work?

Transthyretin (TTR) inhibitors represent a significant advancement in the treatment of diseases associated with protein misfolding and amyloid deposition. As scientists and medical practitioners strive to combat these complex conditions, TTR inhibitors offer a promising avenue for therapeutic intervention. This article delves into the fundamentals of TTR inhibitors, their mechanisms of action, and their therapeutic applications.

Transthyretin (TTR) is a protein primarily produced in the liver and choroid plexus of the brain. It functions predominantly as a transporter of thyroxine and retinol-binding protein in the bloodstream. However, under certain genetic and environmental conditions, TTR can misfold and aggregate, leading to the formation of amyloid fibrils. These fibrils can deposit in various tissues, causing a group of disorders known as transthyretin amyloidosis (ATTR). TTR inhibitors are designed to prevent the misfolding and aggregation of TTR, thereby mitigating the progression of these debilitating diseases.

TTR inhibitors work by stabilizing the TTR tetramer, which is the native quaternary structure of the protein. In its stable form, TTR is composed of four identical subunits that function together. However, genetic mutations or age-related changes can destabilize the tetramer, causing it to dissociate into monomers. These monomers are prone to misfolding and aggregation, leading to the formation of amyloid fibrils. TTR inhibitors bind to the tetramer and enhance its stability, thereby preventing dissociation and subsequent amyloid formation.

There are several classes of TTR inhibitors, including small-molecule stabilizers and antisense oligonucleotides. Small-molecule stabilizers, such as tafamidis and diflunisal, bind directly to the TTR tetramer and increase its stability. These compounds occupy specific binding sites on the protein, thereby preventing it from dissociating into monomers. Antisense oligonucleotides, on the other hand, work by reducing the production of TTR protein. These molecules bind to the mRNA encoding TTR and promote its degradation, thereby decreasing the overall levels of TTR in the bloodstream.

TTR inhibitors are primarily used for the treatment of ATTR, which is classified into two main types: hereditary ATTR (hATTR) and wild-type ATTR (wtATTR). hATTR is caused by mutations in the TTR gene, leading to the production of unstable TTR variants that are more prone to misfolding and aggregation. wtATTR, also known as senile systemic amyloidosis, occurs due to age-related changes in the TTR protein that result in amyloid deposition.

One of the most well-known TTR inhibitors is tafamidis, which has been approved for the treatment of both hATTR and wtATTR. Tafamidis has been shown to significantly reduce amyloid deposition and improve clinical outcomes in patients with ATTR. Clinical trials have demonstrated that tafamidis can slow the progression of neuropathy and cardiomyopathy, two major manifestations of ATTR. Diflunisal, another small-molecule stabilizer, has also shown promise in reducing amyloid deposition and improving clinical outcomes in patients with ATTR.

Antisense oligonucleotides, such as inotersen and patisiran, have also been approved for the treatment of hATTR. These agents have been shown to significantly reduce TTR levels in the bloodstream, thereby reducing amyloid deposition and improving clinical outcomes. Clinical trials have demonstrated that inotersen and patisiran can slow the progression of neuropathy and improve quality of life in patients with hATTR.

In conclusion, TTR inhibitors represent a promising therapeutic strategy for the treatment of ATTR. By stabilizing the TTR tetramer or reducing TTR production, these agents can prevent amyloid formation and mitigate the progression of disease. The development and approval of TTR inhibitors such as tafamidis, diflunisal, inotersen, and patisiran underscore the potential of these agents to improve the lives of patients with ATTR. As research in this field continues to advance, it is likely that new and more effective TTR inhibitors will be developed, offering hope to patients suffering from these challenging conditions.