Amyloid is a protein that builds up in the liver, spleen, and other tissues. When amyloid folds incorrectly, the protein sticks together and forms fibrous deposits in and around cells, causing amyloidosis. Fortunately, affected patients are benefitting from new, cutting-edge treatment options.

What It Is

Amyloidosis is a rare disease that occurs when amyloid builds up in organs. This amyloid buildup can cause organs to stop working correctly. Organs that may be affected include the heart, kidneys, liver, spleen, nervous system, and digestive tract.

Understanding The Wider Scope

Some proteins and proteins with specific mutations are more prone to misfolding and creating insoluble fibers, or amyloid fibrils, that are difficult for cells to break down. Two common examples of amyloid protein are:

• Amyloid beta is associated with Alzheimer’s disease.
• Transthyretin (TTR) transports thyroid hormones and vitamin A in the bloodstream.

Why It Matters

Amyloid fibrils interfere with the normal functioning of cells. Mutations in TTR, for example, cause the protein to form fibrils, which accumulate in the heart and nervous system, causing symptoms such as:

• Cardiomyopathy, an irregular heartbeat and heart failure
• Tingling, numbness, or pain
• Weakness and less mobility
• Digestion and kidney complications

The constellation of nervous system symptoms observed in amyloidosis is called polyneuropathy, caused by damage to tactile nerves and nerves responsible for controlling various organs. And while mutations in the TTR gene are rare, 10 to 20 percent of elderly people experience transthyretin amyloidosis (ATTR)-associated cardiomyopathy despite having no mutation in the TTR gene.

Applications In Action

Drugs approved by the FDA to treat the polyneuropathy associated with mutations in TTR include:

• Onpattro (Alnylam Pharmaceuticals) and Tegsedi (Ionis Pharmaceuticals) reduce mutated TTR production by destroying the gene’s RNA. Less mutated transthyretin protein means fewer amyloid fibrils, reducing polyneuropathy.
• Vyndamax (Pfizer) is a small molecule drug that helps transthyretin fold correctly, resulting in fewer amyloid fibrils. Vyndamax is also used to halt the progression of ATTR-associated cardiomyopathy in patients without TTR gene mutations.

All three treatments lower the deposit of amyloid fibrils to slow disease progression. No current treatment removes the amyloid fibrils that cause ATTR.

Cocktail Fodder

In 2023, the FDA approved the antibody therapy Leqembi (Biogen) to slow the progression of mild Alzheimer’s Disease (AD). The drug binds to amyloid beta to reduce amyloid plaques in the brain, a hallmark of AD. Biogen is also developing new AD treatments aimed at decreasing aggregation of tau protein, which is also associated with AD progression.

• BIIB080 decreases tau production
• BIIB113 decreases the aggregation of tau