Transthyretin (TTR) is a protein, mainly produced by the liver. The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. ₍₂₎ In the case of Transthyretin Amyloidosis, TTR proteins (in the form of a tetramer) separate into individual monomers and become misfolded. The misfolded proteins aggregate into amyloid fibrils which deposit throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastrointestinal, etc. in nature.

The two main types of ATTR are Wild Type and Hereditary. Wild Type Amyloidosis is a disorder predominately of older men in their 70s and beyond. Hereditary Amyloidosis is associated with an inherited genetic mutation.

The four main types of treatments for ATTR, either currently available or in development, consist of stabilizers, silencers, depleters, and gene editors. Note the treatments discussed below include those that are FDA-approved at the time of writing; new FDA-drugs will likely become available in the future.

 

Stabilizers 

TTR stabilization therapy aims to prevent misfolding/destabilization of TTR as shown circled in blue on the illustration below.

 

There are several TTR stabilization therapies available, including acoramidis, tafamidis, and diflunisal.

Acoramidis (AG10) binds to TTR at thyroxine binding sites and slows dissociation of the TTR tetramer. ₍₅₎ Acoramidis was approved by the FDA in 2024 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, twice per day.

Tafamidis binds to the TTR and stabilizes the TTR tetramer, thus slowing misfolding and inhibiting the formation of amyloid fibrils. ₍₄₎ Tafamidis was FDA approved in 2019 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, once per day.

Diflunisal is a non-steroid anti-inflammatory (NSAID) drug, primarily used to treat pain associated with arthritis, but can be used “off-brand” as a TTR stabilizer.  A study proved that diflunisal prevented amyloid fibril formation by tying TTR binding sites in a similar manner to tafamidis. Diflunisal has been shown to halt disease progression and improve quality of life. ₍₃₎

Silencers

In the case of hereditary amyloidosis, TTR silencer therapy aims to prevent destabilization of TTR by silencing errant “messenger RNA” signals. There are multiple silencing therapies available, including patisiran,vutrisiran, inotersen, and eplontersen.

An illustration of the silencing process associated with vutisiran is shown below. The process utilizes small interfering RNAs (siRNA) which results in a single stranded RNA which cleaves the messenger RNA, thus destroying it. ₍₇₎₍₈₎

 

Vutisiran is a newer version of patisiran. It is given as an injection once every three months and must be administered at a healthcare facility. Vutisiran is currently FDA approved for ATTR with polyneuropathy, however, recent clinical trial results show promising data associated with treatment of cardiomyopathy.

Eplontersen is a newer version of inotersen and is FDA approved for polyneuropathy. It can be self-administered monthly via an auto-injector at home. A clinical trial for its use in the treatment of cardiomyopathy is ongoing.

Since TTR proteins serve to transport retinol, a vitamin A supplement must be prescribed to patients using silencer therapy.

Depleters

Also known as antibody therapies, there are a number of treatments currently under development that are designed to remove amyloid that has been deposited in bodily organs and tissue, including

ALXN-2220, AT02, NNC6019.

For example, ALXN-2220 is an investigational antibody that incorporates a fundamental mechanism of the human immune system. The ALXN-2220 antibody specifically targets insoluble ATTR fibrils, eliminating ATTR by activating immune cells which ingest and destroy cellular debris. ₍₆₎

Gene Editors

In the field of genome engineering, the term “CRISPR” is often used loosely to refer to the various systems that can be programmed to target specific stretches of genetic code and to edit DNA at precise locations. With this system, genes in living cells are permanently modified, allowing for the correction of mutations at precise locations in the human genome. ₍₉₎

CRISPR NTLA-2001 is a form of gene editing, currently in clinical trial, that is designed to edit mutated DNA associated with hereditary amyloidosis. This therapy would be a one-time treatment to remove the area of the DNA with the mutation in the liver cells producing the TTR.

… And More

Looking ahead, research of new treatments is active and exciting. The future looks brighter than ever for ATTR patients!

For further information on this paper’s subject matter, please view:

ATTR Amyloidosis Treatments: Stabilizers and Silencers

CRISPR/Cas9 – Editing the Code of Life

 

 

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