How Do Rheumatologic Antisense Oligonucleotides Work?

Antisense oligonucleotides are medications to treat transthyretin (TTR) amyloidosis, a condition caused by hereditary mutation in TTR gene that encodes the TTR protein. Transthyretin amyloidosis affects multiple organs including peripheral nerves, heart, eyes, kidneys, thyroid, bone marrow, gastrointestinal and central nervous systems.

Transthyretin is a soluble protein synthesized by the liver that helps transport vitamin A (retinol) and thyroid hormone (thyroxine) in the body. In people with transthyretin amyloidosis, TTR proteins become insoluble fibers (fibrils) resistant to degradation and build up in tissues of multiple organs, interfering with their normal functioning.

Antisense oligonucleotides bind to the TTR protein’s messenger RNA (mRNA), which is vital for the protein’s synthesis, preventing the synthesis of the mutant protein in the liver, which results in the reduction of TTR protein in blood and TTR deposits in tissues.

Antisense oligonucleotides are administered as subcutaneous injections into the tissue under the skin, approved by the FDA for the treatment of adults with polyneuropathy (damage to multiple peripheral nerves) associated with hereditary transthyretin amyloidosis (hATTR).

Side effects of antisense oligonucleotides may include the following:

• Injection site reactions
• Nausea
• Headache
• Fatigue
• Thrombocytopenia (low platelet count in the blood)
• Fever
• Peripheral edema
• Chills
• Anemia (low blood red cell count)
• Vomiting
• Myalgia (muscle pain)
• Decreased renal function
• Arrhythmia (irregular heart rhythm)
• Arthralgia (joint pain)
• Presyncope or syncope (feeling faint or fainting)
• Decreased appetite
• Paresthesia (prickling sensation)
• Dyspnea (shortness of breath)
• Elevated liver function test
• Orthostasis/orthostatic hypotension (drop in blood pressure when standing up from sitting or lying down)
• Influenza-like illness
• Contusion
• Bacterial infection
• Eosinophilia (high blood level of eosinophils, type of immune cells)
• Dry mouth

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of the FDA-approved antisense oligonucleotide drug are:

• inotersen
• Tegsedi