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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

Bibliography

Sperry, Brett, “Expert Insights Into Amyloidosis, ATTR Amyloidosis Treatments: Stabilizers and Silencers,” Amyloidosis Speakers Bureau, 2024. https://drive.google.com/file/d/1qoAETBYDjDj3zHzxqqxHvAfoq1sfiuEd/view

“Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis

Morfino, P., Aimo, A., Vergaro, G., Sanguinetti, C., Castiglione, V., Franzini, M., Perrone, M. A., & Emdin, M. (2023). Transthyretin stabilizers and seeding inhibitors as therapies for amyloid transthyretin cardiomyopathy. Pharmaceutics, 15(4), 1129. https://doi.org/10.3390/pharmaceutics15041129

Coelho, T., Merlini, G., Bulawa, C. E., Fleming, J. A., Judge, D. P., Kelly, J. W., Maurer, M. S., Planté-Bordeneuve, V., Labaudinière, R., Mundayat, R., Riley, S., Lombardo, I., & Huertas, P. (2016, June). Mechanism of action and clinical application of Tafamidis in hereditary transthyretin amyloidosis. Neurology and therapy. https://pmc.ncbi.nlm.nih.gov/articles/PMC4919130/

National Institutes of Health. (n.d.). DailyMed – ATTRUBY- acoramidis hydrochloride tablet, film coated. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=913552ef-875d-4cb7-bf05-a7d20a394c38

Michalon, A., Renaud, L., Machacek, M., Cortijo, C., Udata, C., Mercuri, M. F., Buller, F., Hock, C., Nitsch, R. M., Kahr, P. C., & Grimm, J. (2024). Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling. Clinical Pharmacology and Therapeutics, 117(1), 261. https://doi.org/10.1002/cpt.3455

“What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.

“RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai

Questions and answers about CRISPR. @broadinstitute. (2014, December 17). https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr

Attruby (Acoramidis), was approved by the FDA on November 22, 2024 for ATTR-CM patients (both wild-type and hereditary) in the U.S.

Orally-administered, Attruby is a near complete TTR stabilizer (>= 90%), designed to reduce cardiovascular death and cardiovascular-related hospitalization. In addition, Attruby has been shown to preserve the native function of TTR as a transport protein of thyroxine and vitamin A.

To honor the courage of our U.S. clinical trial participants, BridgeBio will provide these patients Attruby free for life.

Attruby

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ForgingBridges: Patient Support Services

“Echocardiography is a powerful tool for evaluating cardiac structure and function and is central to the detection and monitoring of disease,” Ross Upton, PhD, CEO and founder of Ultromics, said in a statement. “However, there are some diseases that are very challenging for even the most expert clinician to detect on an echocardiogram. Requiring only a single apical four-chamber image, EchoGo Amyloidosis identifies cardiac amyloidosis and will help drive earlier access to appropriate treatment and care for patients with this underdiagnosed disease.”

LEARN MORE ABOUT EchoGo Amyloidosis

Over the course of the past few months, we spent time discussing two of the most common hallmark symptoms of ATTR amyloidosis: cardiomyopathy and peripheral neuropathy. In this article, we’ll briefly recap both hallmark symptoms as well as bring it all together by discussing the two most common forms of ATTR amyloidosis: ATTR cardiomyopathy (ATTR-CM) and ATTR peripheral neuropathy (ATTR-PN).

To recap …

Cardiomyopathy

Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It is a common cause of sudden cardiac arrest and sudden cardiac death, which can lead to heart failure and even death.

Types of Cardiomyopathy:

Dilated Cardiomyopathy → dilation of the left ventricle prevents the heart from pumping effectively
Hypertrophic Cardiomyopathy → abnormal thickening of the heart muscle most commonly surrounding the left ventricle
Restrictive Cardiomyopathy → stiffening of the heart muscle results in an inelasticity
Arrhythmogenic Right Ventricular Dysplasia → scar tissue replaces healthy tissue of the right ventricle
Unclassified Cardiomyopathy → all other forms of cardiomyopathy fall within this category

Peripheral Neuropathy

Peripheral neuropathy, also referred to as polyneuropathy, is a very broad term used to describe damage of the peripheral nerves. Damage to these nerves most commonly causes numbness, pain, and weakness but can affect other areas of the body including, but not limited to, circulation, digestion, and urination.

Types of Neuropathy:

Motor Neuropathy → damage to the motor nerves
Sensory Neuropathy → damage to sensory nerves
Autonomic Nerve Neuropathy → damage to autonomic nerves that control involuntary functions
Combination Neuropathies → damage to a mix of 2 or 3 of these other types of neuropathies

ATTR Amyloidosis

The origin of this disease can be genetic (hATTR) or non-genetic, or “wild-type” (ATTRwt). Regardless, in ATTR amyloidosis, the transthyretin (TTR) protein is misfolded and aggregates, forming amyloid fibers that deposit into tissues and organs. The deposition of protein causes organ dysfunction and can even cause organ failure and death.

ATTR-CM and ATTR-PN

Depending on the location of protein deposition, the disease is referred to in different ways. For instance, when the primary location of amyloid deposit is in the heart, the disease is referred to as ATTR cardiomyopathy (ATTR-CM). On the other hand, when the primary location of amyloid deposit is in the nerves, the disease is referred to as ATTR peripheral neuropathy (ATTR-PN).

ATTR-CM impairs the heart’s ability to pump effectively. A major challenge surrounding this disease is that symptoms of ATTR-CM are often similar to other heart conditions like enlarged heart and heart failure. This makes diagnosing the disease increasingly more difficult. Individuals with hATTR typically present symptoms in their 50s and 60s, whereas those with ATTRwt may not present symptoms until their 70s and later.

Common Symptoms of ATTR-CM:

Fatigue
Swelling of legs, ankle, or abdomen
Shortness of breath with activity
Orthostatic hypotension
Difficulty breathing when lying down
Arrhythmia

ATTR-PN impairs the function of the nervous system. While amyloid most commonly builds up in the peripheral nervous system, deposition can also occur in the autonomous system. This results in a diversity of symptoms that are specific to the site of amyloid deposition. Symptom presentation is much more diverse, occurring as early as the 20s, or as late in life as the 70s.

Common Symptoms of ATTR-PN:

Carpal tunnel syndrome
Diarrhea and/or constipation
Nausea, vomiting
Loss of appetite
Sexual dysfunction
Muscle weakness
Eye problems
Orthostatic hypotension

Expert Insights – Cardiac Clues and Clinical Signs

In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next, he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.

In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner, from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.

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References:

https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.yourheartsmessage.com

https://healthjade.net/familial-amyloidosis/

https://my.clevelandclinic.org/health/diseases/14737-neuropathy

https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-neuropathy

https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061

https://practicalneurology.com/articles/2021-july-aug/neuromuscular-amyloidosis

https://healthjade.net/familial-amyloidosis/

Dr. J. Mark Sloan, Associate Professor of Medicine, Boston University Chobanian & Avedisian School of Medicine. He is a member of the BU Amyloidosis Center, the Evans Center for Interdisciplinary Biomedical Research at BU, and the program director for the hematology/oncology fellowship at Boston University. In this video, developed exclusively for the Amyloidosis Speakers Bureau, he provides a comprehensive clinical overview of diagnosing amyloidosis, from cardiology to neurology, and when to think about amyloidosis.

Dr. Heather Landau, Associate Attending Physician at Memorial Sloan Kettering, provides a comprehensive clinical overview of amyloidosis. Spanning recognition and diagnosis – the key to successful treatment.

Neuropathy, also known as peripheral neuropathy, is a broad term that is used to describe damage to the nerves outside of the brain and spinal cord. There are over 100 types of peripheral neuropathy that can be classified into four categories, with each type having their own symptoms and prognosis. In this article, we’ll discuss the types of peripheral neuropathy and its connection to amyloidosis.

Symptoms

One of the challenges with neuropathy is the fact that symptoms can vary significantly based on what nerve is damaged. Additionally, symptoms can develop over the course of months to years (chronic neuropathy) or come on suddenly (acute neuropathy). Some of the most commonly seen symptoms are listed below:

Muscle weakness
Cramps
Muscle twitching
Loss of muscle and bone
Changes in skin, hair, or nails
Numbness
Loss of sensation or feeling in body parts
Loss of balance or other functions as a side effect of the loss of feeling in the legs, arms, or other body parts
Emotional disturbances
Sleep disruptions
Loss of pain or sensation that can put you at risk, such as not feeling an impending heart attack or limb pain
Inability to sweat properly, leading to heat intolerance
Loss of bladder control, leading to infection or incontinence
Dizziness, lightheadedness, or fainting because of a loss of control over blood pressure
Diarrhea, constipation, or incontinence related to nerve damage in the intestines or digestive tract
Trouble eating or swallowing
Life-threatening symptoms, such as difficulty breathing or irregular heartbeat

Types of Neuropathy

Motor Neuropathy → Damage to the motor nerves control how you move.
Sensory Neuropathy → Damage to sensory nerves control what you feel.
Autonomic Nerve Neuropathy → Damage to autonomic nerves that control functions that are involuntary (ie. you do not consciously control).
Combination Neuropathies → Damage to a mix of 2 or 3 of these other types of neuropathies. For example, damage to both sensory and motor nerves would result in sensory-motor neuropathy.

Amyloidosis

Peripheral Neuropathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-PN, or transthyretin amyloid polyneuropathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the nerve tissue, resulting in damage to these nerves. While amyloid deposits primarily in the peripheral nerves, it is not uncommon for amyloid deposition in the autonomic nerves as well.

While peripheral neuropathy is most commonly associated with ATTR amyloidosis, it should be noted that peripheral neuropathy is also seen in 15-35% of patients with AL amyloidosis.

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

Neurological Complications of ATTR Amyloidosis

Patients with ATTR amyloidosis are commonly faced with neurological complications. In this presentation, Dr. Chafic Karam from the University of Pennsylvania goes through four areas: an overview of the neurological systems, how amyloid damages the nerves, neurological signs of ATTR amyloidosis, and how to detect amyloid and diagnose ATTR amyloid neuropathy.

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References:

https://my.clevelandclinic.org/health/diseases/14737-neuropathy

https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-neuropathy

https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061

https://practicalneurology.com/articles/2021-july-aug/neuromuscular-amyloidosis

https://healthjade.net/familial-amyloidosis/

Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It can lead to heart failure and even death. In this article, we’ll discuss the types of cardiomyopathy and its connection to amyloidosis.

Risk Factors

It has no ideal target, as it can affect a person of any age, race, or gender. However, there are a number of risk factors that can put one at an increased chance of developing cardiomyopathy.

Genetic History → Family history of cardiomyopathy, heart failure, or sudden cardiac arrest
High Blood Pressure → Over a long period of time
Heart Conditions → Past history of heart attack, coronary artery disease, or infection of the heart
Obesity → Tends to make the heart work harder to perform its normal function
Alcohol Use → Long period of alcohol use
Drug Use → Use of illicit drugs, such as cocaine, amphetamines, and anabolic steroids
Medications → Drugs used in the treatment of cancer, such as chemotherapy and radiation

Additionally, there are a number of diseases that increase the risk of developing cardiomyopathy, including:

Amyloidosis
Connective Tissue Disorders
Diabetes
Hemochromatosis (excess iron storage)
Sarcoidosis
Thyroid Disease

Types of Cardiomyopathy

Dilated Cardiomyopathy → Dilation of the left ventricle prevents the heart from pumping effectively. It most commonly occurs in middle-aged men and is typically the result of coronary artery disease, heart attack, or genetic defects.

Hypertrophic Cardiomyopathy → Abnormal thickening of heart muscle, most commonly affecting the muscles surrounding the left ventricle. This type of cardiomyopathy is strongly associated with a family history of the disease. There have been genetic mutations linked specifically with this type of cardiomyopathy.

Restrictive Cardiomyopathy → Stiffening of the heart muscle results in an inelasticity, making it difficult for the heart to expand and fill. It is most commonly seen in the elder population. The disease can be of idiopathic origin or of disease such as amyloidosis. This is the least common type of cardiomyopathy.
Arrhythmogenic Right Ventricular Dysplasia → Scar tissue replaces healthy tissue of the right ventricle. This form of cardiomyopathy is rare and often the result of genetic mutations.
Unclassified Cardiomyopathy → All other forms of cardiomyopathy fall within this category.

Amyloidosis

Cardiomyopathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-CM, or transthyretin amyloid cardiomyopathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the heart muscle, resulting in thickening and stiffening of the heart.

The two types of ATTR-CM are wild-type ATTR-CM (wtATTR) or hereditary ATTR-CM (hATTR). wtATTR-CM is the most common form of ATTR-CM, affecting predominantly white males 60+ years old. hATTR-CM is genetic affecting both men and women, and presents as early as 50+ years old. Interestingly, one of the mutations causing hATTR, V122I, is seen almost exclusively in individuals of African ancestry. It is believed that approximately 3-4% of African Americans carry this mutation, regardless of whether or not they develop symptoms.

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

Expert Insights – Cardiac Clues and Clinical Signs

In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.

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References:

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.yourheartsmessage.com

https://healthjade.net/familial-amyloidosis/

Dr. Sarah S. Lee, Assistant Professor, Division of Hematology, at the City of Hope, provides a brief yet comprehensive clinical overview of amyloidosis. In this video Dr. Lee discusses the breadth of amyloidosis, the wide range of symptom presentations, and which organs are typically involved. Focusing on AL (light chain) and TTR (transthyretin) types, she then goes through a diagnostic workup to arrive at a diagnosis, stressing the importance of typing once the presence of amyloid has been confirmed. Concluding her overview, Dr. Lee describes treatments available and how they impact patient prognosis and quality of life.

Dr. Mazen Hanna, cardiologist at the Cleveland Clinic and co-director of the Amyloid Program, explains how cardiac amyloidosis can originate from two very different types of amyloidosis: AL or ATTR. Dr. Hanna illustrates how physicians can identify cardiac amyloidosis and look to different diagnostic work-ups to understand whether the issues are due to AL or ATTR amyloidosis. These two conditions are treated differently and have different prognoses, emphasizing the importance of understanding the type of amyloidosis involved.

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Transthyretin Amyloidosis (ATTR) Treatments: Stabilizers, Silencers, Depleters, and More!

ATTRUBY (acoramidis) is now FDA-APPROVED for ATTR-CM in U.S.

FDA CLEARS AI SCREENING TOOL FOR CARDIAC AMYLOIDOSIS

ATTR-CM (cardiomyopathy) vs ATTR-PN (peripheral neuropathy)