Amyloid deposits are not only present in the brains of cognitively impaired individuals but also accumulate throughout the body, impairing organ function and causing damage and disease. Therefore, the development of amyloid-targeting therapies has gained increasing attention, not only to treat Alzheimer’s disease, where amyloid plaques are the main pathological hallmark, but also to address other diseases, including heart failure and the systemic amyloidosis.
Amyloid Fibril Formation: The Molecular Pathway Driving Pathophysiology
To date, approximately “amyloidogenic” proteins have been identified. These proteins are inherently prone to misfolding and aggregation into amyloid fibrils. Despite being structurally and functionally different, they share a characteristic β-sheet structure. Under normal physiological conditions, these proteins exist in a state of equilibrium between properly folded and misfolded forms. When the balance tips towards misfolding, cells rely on an internal quality control mechanism — the Unfolded Protein Response (UPR) — to prevent amyloid formation. However, when this system is overwhelmed, amyloid fibrils can accumulate in various tissues, such as the heart, liver, kidneys, gastrointestinal tract leading to tissue amyloidosis. More than 15 different forms of systemic amyloidosis have been identified, often linked to aging or genetic mutations. One well-known example of hereditary amyloidosis is associated with mutations in the transthyretin (TTR) protein, a tetrameric protein produced in the liver and secreted into plasma to transport the hormone thyroxine and retinol (vitamin A). Clinical symptoms of amyloidosis are typically insidious and nonspecific, making amyloid typing challenging. Interestingly, some forms of amyloidosis have been observed to reverse spontaneously, although this is extremely rare and not yet well understood.
Current and Future Therapeutic Approaches to Treat Systemic Amyloidosis
To prevent the toxic buildup of amyloid-β in tissues, several therapeutic strategies have been developed:
- Antibodies Targeting Misfolded Transthyretin: Potent antibodies, such as ALXN2220 and Anselamimab, developed by AstraZeneca, are in phase 3 trials for treating ATTR amyloidosis.
- Stabilizing Agents: These agents selectively bind and stabilize transthyretin in its functional tetrameric state, reducing its rate of dissociation into aggregation-prone monomers. The first ATTR stabilizer, Tafamidis, is now Pfizer’s third-best-selling drug. In late November, the FDA is expected to decide on the approval of BridgeBio’s Acoramidis, another transthyretin stabilizer for treating amyloidosis with cardiomyopathy (ATTR-CM).
- Transthyretin Silencers: Four silencing drugs have been approved for ATTR with polyneuropathy. Alnylam Pharmaceuticals has developed two siRNA drugs (Onpattro and Amvuttra), while Ionis Pharmaceuticals has created two antisense oligonucleotide-based silencers (Wainua and Tegsedi). Additionally, Intellia Therapeutics has developed a CRISPR–Cas9-based therapy targeting the TTR locus in liver cells to achieve more potent and sustained silencing effects. This therapy, delivered via lipid nanoparticles and administered in vivo, will soon enter a phase 3 clinical trial.
Beyond targeting transthyretin, researchers aim to develop therapies that can bind all forms of amyloid, irrespective of the specific misfolded protein. Attralus, for example, is exploring AT-02, a humanized IgG1 monoclonal antibody fused with a proprietary pan-amyloid binding peptide. This innovative approach is designed to stimulate macrophage-mediated phagocytosis and facilitate the removal of amyloid deposits. In conclusion, amyloid diseases are part of a larger group of disorders characterized by protein misfolding. Although a functional cure for systemic amyloidosis remains a distant goal, significant progress is being made. In the coming years, biotech companies are expected to bring transformative changes to the treatment landscape of amyloidosis, making it a very different field from what it is today.
By Annarita D’Urso, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan
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Link: https://www.nature.com/articles/s41587-024-02471-1 Doi: https://doi.org/10.1038/s41587-024-02471-1