How Do RNAi Agents Work?

RNA interference (RNAi) agents are a collection of small RNA molecules that are used to treat rare genetic disorders. These drugs work by inducing sequence-specific inhibition of target gene expression or translation of RNA that is responsible for the genetic disorder.

RNAi agents are gene-specific drugs.

Givosiran is 5-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) that downregulates ALAS1 messenger RNA (mRNA) and prevents the accumulation of neurotoxic delta-aminolevulinic acid and porphobilinogen levels that are associated with acute porphyria.

Lumasiran is an interfering RNA that silences the gene hydroxyacid oxidase 1 (HOA1). It targets HOA1 mRNA and prevents its translation to the enzyme glycolate oxidase (GO). In the absence of GO, glyoxylate is reduced and not available for the metabolism of oxalate. Patients with primary hyperoxaluria type 1 produce an excess amount of oxalate because of deficiency of enzyme alanine-glyoxylate aminotransferase.

Patisiran is a transthyretin-directed siRNA used to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis. This drug binds to wild-type transthyretin (TTR) mRNA and degrades it; thus, the levels of serum and tissue TTR protein deposits are decreased.

RNAi agents are given as intravenous or subcutaneous injections for the following:

• Acute hepatic porphyria
• Hyperoxaluria type 1
• Polyneuropathy of hereditary transthyretin-mediated amyloidosis

Side effects of RNAi agents may include:

• Nausea
• Injection site reactions
• Upper respiratory tract infections
• Shortness of breath
• Fatigue
• Muscle spasms
• Joint pains
• Abdominal pain
• Kidney dysfunction
• Increased serum creatinine
• Liver failure
• Elevated liver enzymes
• Heart block
• Vertigo (spinning sensation)
• Hypotension (low blood pressure)
• Syncope
• Blurred vision
• Anaphylaxis (life-threatening allergic reactions)

The 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 RNAi agents include:

• Givosiran (Givlaari)
• Lumasiran (Oxlumo)
• Patisiran (Onpattro)