A New Era in Treating Transthyretin Amyloidosis: RNA Interference Therapy
Transthyretin amyloidosis (ATTR) is a rare, progressive disease caused by the misfolding and buildup of transthyretin (TTR) protein as amyloid deposits in various tissues. While some cases are linked to genetic mutations (hereditary ATTR, or hATTR), a significant portion occurs without a known genetic cause – termed wild-type ATTR (ATTRwt). Both forms can lead to serious complications, particularly affecting the heart and nerves. Historically, treatment options were limited, but recent advances in RNA interference (RNAi) therapy are dramatically changing the landscape of ATTR management.
ATTR affects an estimated one in 100,000 people overall. ATTRwt, linked to aging, is often underdiagnosed, affecting approximately 1% of men over the age of 80, with an average diagnosis age around 75. The disease is systemic, meaning amyloid deposits can form throughout the body. Cardiac involvement, where deposits stiffen the heart walls, can lead to rhythm disturbances and heart failure. Carpal tunnel syndrome can sometimes be an early indicator of the condition.
Traditionally, liver transplantation was the standard treatment for ATTR, aiming to reduce the production of the abnormal TTR protein, as the liver is the primary source of TTR production. However, the arrival of RNAi therapies has revolutionized treatment, particularly for hATTR.
RNAi therapies leverage a natural cellular process to specifically target messenger RNA (mRNA) – the molecule that carries instructions for building proteins. In the context of ATTR, these treatments target the mRNA coding for TTR synthesis, effectively blocking the production of the misfolded protein at its source. This approach differs from gene therapy as it acts on the mRNA, a temporary copy of DNA, without altering the underlying genetic code.
While RNAi therapy doesn’t eliminate existing amyloid deposits, it stabilizes the disease by preventing the formation of new ones. Consequently, treatment must be continued long-term, as halting therapy allows TTR production to resume and disease progression to restart. Early intervention following diagnosis is crucial to maximize benefit.
These therapies exhibit a high degree of specificity, primarily acting on liver cells where TTR is produced, minimizing off-target side effects. Furthermore, the vectors used to deliver the RNAi are biodegradable, reducing the risk of long-term accumulation and liver toxicity.
with over a decade of clinical experience, RNAi treatments have demonstrated effectiveness, reliability, and a favorable safety profile in managing hATTR. Their ease of management – via simple subcutaneous injection – and safety make them a leading therapeutic option for hATTR, and research is ongoing to explore their potential request in treating wild-type ATTR as well.
(This article reflects information presented in the provided text and does not include any external sources or speculative information.)
