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The Use of RNA Interference Science in the Treatment of Hereditary Amyloidosis

Hereditary transthyretin amyloidosis (hATTR) is a severe, adult-onset inherited systemic disease which can affect the peripheral and autonomic nervous system, heart, kidney and the eyes. (1)

TTR (transthyretin) is a protein found in blood plasma and blood serum as well as in the cerebrospinal fluid (CSF). The protein is mainly synthesized (assembled) by the liver and the choroid plexus (CP). The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. The protein is created by a process called biosynthesis. Biosynthesis is carried out in accordance with genetic instructions encoded from ones DNA. The DNA instructions create messenger RNA (mRNA), which in turn biosynthesize transthyretin proteins in the form of a tetramer. (2)

In the case of hereditary amyloidosis, a DNA mutation causes an errant mRNA signal, which results in destabilization of the tetramer and misfolding of the protein. The misfolded TTR proteins aggregate into amyloid fibrils as shown in the figure below. (3) The Amyloid then deposits throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastro-intestinal, etc. in nature.

 

 

RNA interference (RNAi) is a natural process that controls gene “expression” to messenger RNAs (mRNA), thus blocking the RNA instruction for creating a protein.

The figure shown below illustrates this process. (4) In basic terms, the interfering process begins with a long double-stranded RNA (dsRNA) being “diced” into small fragments by an enzyme called a “Dicer”. These fragments, referred to as small interfering RNAs (siRNA), bind to proteins called argonaute proteins. After binding to an argonaute protein, one strand of the double-stranded RNA is removed. The remaining strand then binds to the targeted messenger RNA. The argonaute protein then cleaves the messenger RNA, destroying it.

 

RNA interfering therapeutic medicines mimic this natural process, utilizing designed small interfering RNAs (siRNA) that ultimately bind to and destroy disease-causing RNA. As a result, the cell is no longer able to produce the misfolded Amyloid protein. One such therapeutic is the drug Vutisiran, used to treat hereditary amyloidosis with polyneuropathy. The figure shown below shows how Vutisiran carries out the same silencing process. (5)

 

 

 

For additional information on ATTR Treatments such as stabilizers and silencers, please view the short Expert Insights video below by Dr. Brett W. Sperry from our Amyloidosis Lecture Series.

 

 

 

 

Sources —————————————–

  1. Carroll, A., Dyck, P. J., Carvalho, M. de, Kennerson, M., Reilly, M. M., Kiernan, M. C., & Vucic, S. (2022, June 1). Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. Journal of Neurology, Neurosurgery & Psychiatry. https://jnnp.bmj.com/content/93/6/668
  1. “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
  1. Diagnostic Algorithm for Transthyretin Amyloidosis with Lower… | Download Scientific Diagram, researchgate.net/figure/Diagnostic-algorithm-for-transthyretin-amyloidosis-with-lower-gastrointestinal_fig1_348081318. Accessed 28 Oct. 2024.
  1. “What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.
  1. “RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai

ATTR Amyloidosis Treatments: Stabilizers and Silencers

Dr. Brett Sperry, cardiologist and director of the Cardiac Amyloidosis Program at Saint Luke’s Mid America Heart Institute, provides an excellent overview of FDA-approved ATTR amyloidosis treatments. He goes into detail about the biology behind silencers and stabilizers and exactly how they impair amyloidosis progression. In addition, he previews the future, summarizing new categories of drugs on the horizon.

Update: In November, 2024 the FDA approved Attruby (Acoramidis) for ATTR-CM (wild-type and hereditary/variant).

The future is indeed exciting!

AL Amyloidosis: The Past, Present, and Future

Dr. Morie Gertz, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, shares his views on the past, present, and future treatments of AL (light chain) amyloidosis. Over his four decades of experience with this disease, he has diagnosed and treated thousands of patients, advanced research, and managed countless clinical trials. This makes him the perfect professor to orate on the dramatic evolution of treating this historically devastating disease to the optimism of today, and the breakthrough world of tomorrow. This is a must-watch video from a legendary expert.

Amyloidosis and the Gut

Dr. Melissa Hershman, assistant professor from the OHSU Division of Gastroenterology & Hepatology, provides an informative overview of how, and where, amyloidosis can present in the G.I. tract. She reviews patient symptoms, many of which are nonspecific and can be associated with other more common issues, delaying diagnosis. Dr. Hershman goes through  how G.I. amyloidosis is tested for, where in the G.I. tract biopsies are most commonly performed, and how the tissue is stained for diagnosis by pathology. In closing, she reviews the array of treatments available to assist patients.

Central Nervous System and Ocular Involvement in hATTR

Dr. Chafic Karam, professor of neurology from the University of Pennsylvania, provides an informative overview of how certain mutations of hereditary transthyretin amyloidosis are being diagnosed in the central nervous system (CNS), such as the eye. It has been long believed that amyloidosis did not cross the blood brain barrier; however, evidence is showing otherwise. In addition, while most of the transthyretin protein originates in the liver, local production is found in other areas of the body such as the brain and retina. Dr. Karam will discuss how patients might present, the developing state of diagnostics, and treatments available. A slower developing symptom, with patients now living longer he predicts neurologists will see more and more patients with CNS and ocular involvement.

Patient Insights: My survival depends on my physicians communicating

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Rayna. She talks about how important she felt it was for her survival that her physicians communicated.

AL Amyloidosis: Symptoms, Diagnostics and Challenges

Dr. Gurbakhash Kaur, co-director of the amyloidosis program at UT Southwestern Medical Center, opens with a brief overview of the disease. Focusing on AL Amyloidosis, she shares how heterogeneously this disease presents – it can be very different from patient to patient, amplifying the diagnostic challenge. Symptoms may also be more commonly associated with other diseases. For example, proteinuria is often associated with diabetes and hypertension. However, clinicians should look at the bigger picture to be sure, as amyloidosis can also be a cause. Dr. Kaur reviews what should be in a basic workup when one has a clinical suspicion for amyloidosis. Once tested positive for amyloidosis, a second necessary step is to determine the type of amyloidosis. This is critical as it will determine the appropriate course of treatment. In closing Dr. Kaur summarizes the goals of treatment, what is available today, and what drugs are in clinical trials, giving lots of hope to the AL amyloidosis community.

Diagnosing Amyloidosis: From Cardiology to Neurology – When to Think About 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.

AL and ATTR Amyloidosis: Recognition and Diagnosis — The Key to Successful Treatment

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.

 

Patient Insights: Not Every Symptom is Amyloidosis

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Dan with his reminder to PCPs — not every symptom is due to amyloidosis!

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