Amyloidosis is a rare, serious condition characterized by the buildup of abnormal protein deposits, called amyloid fibrils, in the body’s tissues and organs. These misfolded proteins accumulate and can eventually impair the function of organs like the heart, kidneys, and liver, leading to life-threatening complications. The disease is often difficult to diagnose because its initial signs are vague and can mimic other common illnesses. Current medical efforts focus on controlling the production of these toxic proteins and managing organ damage to improve patient outcomes.
Is Amyloidosis Curable?
Amyloidosis is not considered “curable” in the traditional sense, meaning the disease is not entirely eradicated with no chance of recurrence. However, this perspective is rapidly evolving due to significant advances in treatment, transforming the condition into one that is often highly treatable and manageable. Treatment goals focus on achieving “deep remission” or “disease control,” where the production of the abnormal protein is stopped, and organ function is stabilized or improved.
Achieving deep remission means the abnormal protein levels are suppressed to a point where disease progression halts, allowing the body to slowly clear existing deposits. Early diagnosis is an important factor in a patient’s prognosis, as aggressive treatment before extensive organ damage occurs leads to the best possible outcomes. While the underlying cause may not be permanently eliminated, modern therapies effectively control the disease, allowing patients to live for many years with a good quality of life.
The Role of Amyloid Type in Treatment
Amyloidosis is not a single disease but rather a group of conditions, each caused by a different precursor protein that misfolds and deposits as amyloid. Identifying the specific protein responsible is the primary step, as the entire treatment strategy is dictated by the type of amyloidosis. The therapeutic approach for one type would be ineffective or even harmful for another, necessitating precise diagnosis.
The three most common systemic types are classified by their precursor protein: AL, ATTR, and AA amyloidosis. AL amyloidosis, the most common type, is caused by abnormal light chain proteins produced by plasma cells in the bone marrow, often associated with multiple myeloma. ATTR amyloidosis involves the transthyretin (TTR) protein, which can be inherited (hereditary) or occur spontaneously with age (wild-type). AA amyloidosis is secondary to chronic inflammatory or infectious diseases, involving the serum amyloid A protein. Because the origin of the toxic protein is distinct for each type, therapies must target the specific source cell or mechanism to be successful.
Halting Amyloid Protein Production
The primary objective of current amyloidosis management is to stop the production of the toxic precursor protein, preventing further organ damage. For AL amyloidosis, treatment centers on eliminating the abnormal plasma cells in the bone marrow that manufacture the light chain proteins. This is achieved using combination chemotherapy drugs, such as daratumumab, bortezomib, cyclophosphamide, and dexamethasone (Dara-CyBorD). These regimens are adapted from therapies used for multiple myeloma and aim for a rapid reduction in the abnormal protein.
For select patients who are otherwise healthy and have less advanced disease, high-dose chemotherapy followed by an autologous stem cell transplant (ASCT) may be an option, which essentially resets the blood-forming system. In ATTR amyloidosis, the approach focuses on the liver, which is the main source of the TTR protein. One strategy uses stabilizer drugs, such as tafamidis, which bind to the TTR protein in the bloodstream, preventing it from misfolding and aggregating into amyloid fibrils.
A second strategy for ATTR is the use of gene-silencing therapies, including small interfering RNAs (siRNAs) like patisiran or antisense oligonucleotides (ASOs) like inotersen. These medications suppress the production of the TTR protein by interfering with the genetic instructions in the liver cells. For AA amyloidosis, treatment is indirect, requiring management of the underlying chronic inflammatory condition, such as rheumatoid arthritis or a long-term infection. By controlling the inflammation, the production of the serum amyloid A protein is reduced, halting disease progression.
Advanced Therapies and Research
Novel approaches to amyloidosis treatment focus on not only stopping protein production but also actively removing existing amyloid deposits. One promising area involves the development of monoclonal antibodies, which are designed to attach to the amyloid fibrils in the organs. These antibodies, such as CAEL-101 for AL amyloidosis or ALXN2220 for ATTR, help the body’s immune system recognize and clear the toxic buildup. This represents a shift toward “depleter” therapies, directly tackling the organ damage that has occurred.
Another research front is gene editing, particularly using CRISPR-Cas9 technology. For ATTR amyloidosis, this technology has been tested to permanently edit the DNA of liver cells, effectively “knocking out” the gene responsible for producing the TTR protein. Early human trials have shown that a single infusion of a CRISPR-based therapeutic can lead to a sustained reduction in circulating TTR protein levels, offering the possibility of a permanent, one-time treatment. These investigational treatments hold the potential to offer a definitive long-term solution for patients.