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Ferrari Chen YF, Aimo A, Castiglione V, Chubuchna O, Morfino P, Fabiani I, Buda G, Emdin M, Vergaro G. Etiological Treatment of Cardiac Amyloidosis: Standard of Care and Future Directions. Curr Heart Fail Rep 2025; 22:16. [PMID: 40232627 PMCID: PMC12000256 DOI: 10.1007/s11897-025-00701-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/21/2025] [Indexed: 04/16/2025]
Abstract
PURPOSE OF REVIEW Cardiac amyloidosis (CA) is a condition caused by interstitial infiltration of misfolded proteins structured into amyloid fibrils. Transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis represent the most common forms of CA. CA was traditionally perceived as a rare and incurable disease, but diagnostic and therapeutic advances have undermined the conventional paradigm. RECENT FINDINGS The standard of care for ATTR-CA include agents capable of selectively stabilizing the precursor protein (e.g., tafamidis), whereas the plasma cell clone is the main target of chemotherapy for AL-CA. For long, tafamidis represented the only drug approved for patients with ATTR-CA. Recent data from ATTRibute-CM led to the approval of acoramidis, whereas patisiran received refusal based on the APOLLO-B trial. Novel CRISPR-Cas9-based drugs (i.e., NTLA-2001) hold great potential in the setting of ATTR-CA. Several hematological regimens are available to treat AL-CA. The main limit of current therapies is their inability to trigger removal of amyloid from tissues. However, the investigation of monoclonal antibodies targeting misfolded ATTR (e.g., PRX004, NI301A) or AL (e.g., birtamimab, anselamimab) has led to encouraging results. Various cutting-edge strategies are being tested for treatment of CA and may change the prognostic landscape of this condition in the next years.
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Affiliation(s)
- Yu Fu Ferrari Chen
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Alberto Aimo
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Vincenzo Castiglione
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Olena Chubuchna
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Paolo Morfino
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Iacopo Fabiani
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Gabriele Buda
- Department of Experimental and Clinical Medicine, University of Pisa, Pisa, Italy
| | - Michele Emdin
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Giuseppe Vergaro
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa, Italy.
- Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna Fondazione Toscana Gabriele Monasterio, via G. Moruzzi 1, Pisa, 56124, Italy.
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Gialamas I, Zakynthinos GE, Dimeas G, Pantelidis P, Gialafos E, Brili S, Goliopoulou A, Katsarou O, Tryfou E, Kalogeras K, Siasos G, Oikonomou E. A Tale of Two Diseases: Decoding Aortic Stenosis and Cardiac Amyloidosis. J Clin Med 2025; 14:2652. [PMID: 40283481 PMCID: PMC12027563 DOI: 10.3390/jcm14082652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/29/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy caused by transthyretin (TTR) amyloid deposition in the myocardium, increasingly recognized in patients with aortic stenosis (AS). This study aims to investigate the diagnostic challenges and therapeutic strategies for patients with both conditions, focusing on shared pathophysiological mechanisms and key diagnostic indicators. Methods: A multimodal diagnostic approach was applied, utilizing cardiac magnetic resonance (CMR) and bone scintigraphy with technetium-99m-labeled tracers to assess AS patients with suspected ATTR-CA. Clinical signs, such as disproportionate heart failure symptoms, conduction abnormalities, and low-flow, low-gradient AS, were evaluated. Electrocardiographic findings, including low-voltage QRS complexes and pseudo-infarction patterns, were also assessed. Treatment options, including transcatheter aortic valve replacement (TAVR) and emerging pharmacotherapies for ATTR-CA, were analyzed. Results: The study found that ATTR-CA is increasingly prevalent in AS patients, with shared mechanisms like oxidative stress and amyloid-induced tissue remodeling. Key diagnostic signs include disproportionate heart failure symptoms, conduction abnormalities, and specific electrocardiographic patterns. TAVR was effective in both isolated AS and AS with ATTR-CA, although patients with both conditions had a higher risk of heart failure hospitalization and persistent symptoms. Emerging pharmacotherapies, such as TTR stabilizers and gene-silencing agents, showed promise in slowing disease progression. Conclusions: A multimodal diagnostic approach is essential for the early detection of ATTR-CA in AS patients. Combining TAVR with emerging pharmacotherapies may improve long-term outcomes for this high-risk group, enhancing patient care in those with both conditions.
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Affiliation(s)
- Ioannis Gialamas
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - George E. Zakynthinos
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - George Dimeas
- Department of Internal Medicine, General Hospital of Karditsa, 43100 Karditsa, Greece;
| | - Panteleimon Pantelidis
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Elias Gialafos
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Styliani Brili
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Athina Goliopoulou
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Ourania Katsarou
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Elsi Tryfou
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Konstantinos Kalogeras
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
| | - Gerasimos Siasos
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.G.); (P.P.); (E.G.); (S.B.); (A.G.); (O.K.); (E.T.); (K.K.); (G.S.); (E.O.)
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Hellenbart EL, Ipema HJ, Rodriguez‐Ziccardi MC, Krishna H, DiDomenico RJ. Disease-modifying therapies for amyloid transthyretin cardiomyopathy: Current and emerging medications. Pharmacotherapy 2025; 45:124-144. [PMID: 39714070 PMCID: PMC11823349 DOI: 10.1002/phar.4639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/24/2024]
Abstract
Transthyretin amyloidosis (ATTR) is a rare disease that results in amyloid fibril misfolding and deposition in multiple organs, including the heart, leading to the development of ATTR cardiomyopathy (ATTR-CM), which is associated with poor outcomes. In the last decade, several disease-modifying medications are in advanced stages of clinical development or have been approved to treat ATTR-CM. The purpose of this review is to critically evaluate clinical trial data investigating the use of approved and investigational medications for the treatment of ATTR-CM. We performed a comprehensive literature search via PubMed and EMBASE to identify randomized controlled trials evaluating medications for the treatment of ATTR-CM published through August 2024. This narrative review describes the pathophysiology of ATTR-CM, highlights important screening and diagnostic work-up, and summarizes the existing clinical evidence resulting from our literature search. Several classes of disease-modifying medications are in development for ATTR-CM. The tetramer stabilizers and transthyretin silencers have proven to be the most effective therapies to date. Tafamidis and acoramidis are currently approved for ATTR-CM while vutrisiran approval for ATTR-CM may be forthcoming. Other disease-modifying medication classes in development include antisense oligonucleotides, gene editing therapies, and monoclonal antibodies. However, several unmet needs exist including the lack of cost-effectiveness due to the extremely high acquisition costs of these medications. Disease-modifying medications approved and in development to treat ATTR-CM offer hope for patients with this disease, but their lack of affordability is the biggest barrier to their use.
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Affiliation(s)
- Erika L. Hellenbart
- Department of Pharmacy PracticeUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Heather J. Ipema
- Department of Pharmacy PracticeUniversity of Illinois ChicagoChicagoIllinoisUSA
| | | | - Hema Krishna
- Department of Medicine, Section of CardiologyUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Robert J. DiDomenico
- Department of Pharmacy PracticeUniversity of Illinois ChicagoChicagoIllinoisUSA
- Center for Pharmacoepidemiology and Pharmacoeconomic ResearchUniversity of Illinois ChicagoChicagoIllinoisUSA
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Sheehan K, Jeon H, Corr SC, Hayes JM, Mok KH. Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease. Protein J 2025; 44:1-20. [PMID: 39527351 DOI: 10.1007/s10930-024-10237-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings.
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Affiliation(s)
- Kate Sheehan
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Hyesoo Jeon
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- Lonza Biologics Tuas Pte. Ltd., 35 Tuas South Ave 6, Singapore, 637377, Republic of Singapore
| | - Sinéad C Corr
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Jerrard M Hayes
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - K H Mok
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
- Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
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Younis M, Ogbu I, Kalra DK. Optimizing drug therapies in cardiac amyloidosis. Pharmacol Ther 2025; 265:108758. [PMID: 39586360 DOI: 10.1016/j.pharmthera.2024.108758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 11/27/2024]
Abstract
Cardiac amyloidosis (CA) is a form of infiltrative, restrictive cardiomyopathy that presents a diagnostic and therapeutic challenge in clinical practice. Historically, it has led to poor prognosis due to limited treatment options. However, advancements in disease awareness, diagnostic tools, and management approaches have led to the beginning of an era characterized by earlier diagnosis and a broader range of treatments. This article examines the advances in treating the two primary forms of cardiac amyloidosis: transthyretin cardiac amyloidosis (ATTR-CA) and light chain mediated cardiac amyloidosis (AL-CA). It highlights therapies for ATTR-CA that focus on interrupting the process of amyloid fibril formation. These therapies include transthyretin stabilizers, gene silencers, and monoclonal antibodies, which have shown the potential to improve patient outcomes and survival rates significantly. As of this writing, tafamidis is the sole Food and Drug Administration (FDA)--approved drug for ATTR-CA; however, experts anticipate several other drugs will gain approval within 1-2 years. Treatment strategies for AL-CA typically involve chemotherapy to inhibit the clonal cell type responsible for excessive AL amyloid fibril production. The prognosis for both types of amyloidosis primarily depends on how much the heart is affected, with most deaths occurring due to progressive heart failure. Effective care for CA patients requires collaboration among specialists from multiple disciplines, such as heart failure cardiology, electrophysiology, hematology/oncology, nephrology, neurology, pharmacology, and palliative care.
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Affiliation(s)
- Mohamed Younis
- Division of Cardiology, University of Louisville Hospital, Louisville, KY, United States of America
| | - Ikechukwu Ogbu
- Division of Cardiology, University of Louisville Hospital, Louisville, KY, United States of America
| | - Dinesh K Kalra
- Division of Cardiology, University of Louisville Hospital, Louisville, KY, United States of America.
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Wang H, Nie Y, Sun Z, He Y, Yang J. Serum amyloid P component: Structure, biological activity, and application in diagnosis and treatment of immune-associated diseases. Mol Immunol 2024; 172:1-8. [PMID: 38850776 DOI: 10.1016/j.molimm.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/09/2024] [Accepted: 05/21/2024] [Indexed: 06/10/2024]
Abstract
Serum amyloid P component (SAP) is a member the innate immune humoral arm and participated in various processes, including the innate immune responses, tissue remodeling, and the pathogenesis of inflammatory diseases. Remarkably, SAP is a highly versatile immunomodulatory factor that can serve as a drug target for treating amyloid diseases and reduce inflammation, fibrosis degree, and respiratory disease. In this review, we focus on the biological activities of SAP and its application in different systemic immune-associated diseases. First, we reviewed the regulatory effects of SAP on innate immune cells and possible mechanisms. Second, we emphasized SAP as a diagnostic marker and therapeutic target for immune-associated diseases, including the neuropsychiatric disorders. Third, we presented several recommendations for regulating SAP in immune cell function and potential areas for future research. Some authorities consider SAP to be a pattern recognition molecule that plays multiple roles in the innate immune system and inflammation. Developing therapeutics that target SAP or its associated signaling pathways may be a promising strategy for treating immune-associated diseases.
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Affiliation(s)
- Haixia Wang
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Yadan Nie
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Zuoli Sun
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Yi He
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China.
| | - Jian Yang
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China.
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Palladini G, Liedtke M, Zago W, Dolan P, Kinney GG, Gertz MA. The mechanism of action, pharmacological characteristics, and clinical utility of the amyloid depleter birtamimab for the potential treatment of AL amyloidosis. Leuk Lymphoma 2024; 65:1068-1078. [PMID: 38600883 DOI: 10.1080/10428194.2024.2337803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/27/2024] [Indexed: 04/12/2024]
Abstract
Amyloid light chain (AL) amyloidosis is a progressive plasma cell disorder caused by amyloid deposition resulting in organ damage and failure. Current standard-of-care treatments target clonal plasma cells, the source of misfolded light chains (amyloid precursors), yet only half of patients with advanced disease survive ≥6 months. The amyloid depleter birtamimab is an investigational humanized monoclonal antibody that binds misfolded κ and λ light chains with high specificity and was designed to neutralize soluble toxic light chain aggregates and promote phagocytic clearance of deposited amyloid. Post hoc analyses from the Phase 3 VITAL trial suggested birtamimab plus standard of care confers a survival benefit in patients with advanced (Mayo Stage IV) AL amyloidosis. AFFIRM-AL (NCT04973137), a Phase 3 confirmatory trial of birtamimab plus standard of care in patients with Mayo Stage IV AL amyloidosis, is ongoing. This review summarizes birtamimab's mechanism of action, attributes, and potential clinical utility.
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Affiliation(s)
- Giovanni Palladini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Amyloidosis Research and Treatment Center, Fondazione IRCCS, Policlinico San Matteo, Pavia, Italy
| | | | | | - Phil Dolan
- Prothena Biosciences Inc, Brisbane, CA, USA
| | | | - Morie A Gertz
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
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Wang J, Li J, Zhong L. Current status and prospect of anti-amyloid fibril therapy in AL amyloidosis. Blood Rev 2024; 66:101207. [PMID: 38692939 DOI: 10.1016/j.blre.2024.101207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/11/2024] [Accepted: 04/14/2024] [Indexed: 05/03/2024]
Abstract
Amyloid light-chain (AL) amyloidosis is a rare hematological disease that produces abnormal monoclonal immunoglobulin light chains to form amyloid fibrils that are deposited in tissues, resulting in organ damage and dysfunction. Advanced AL amyloidosis has a very poor prognosis with a high risk of early mortality. The combination of anti-plasma cell therapy and amyloid fibrils clearance is the optimal treatment strategy, which takes into account both symptoms and root causes. However, research on anti-amyloid fibrils lags far behind research on anti-plasma cells, and there is currently no approved treatment that could clear amyloid fibrils. Nevertheless, anti-amyloid fibril therapies are being actively investigated recently and have shown potential in clinical trials. In this review, we aim to outline the preclinical work and clinical efficacy of fibril-directed therapies for AL amyloidosis.
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Affiliation(s)
- Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jian Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Liye Zhong
- Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
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Karam S, Kaushal A, Abu Amer N, Royal V, KItchlu A. Non-Immunoglobulin Amyloidosis-Mediated Kidney Disease: Emerging Understanding of Underdiagnosed Entities. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:334-345. [PMID: 39084759 DOI: 10.1053/j.akdh.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/24/2024] [Accepted: 02/06/2024] [Indexed: 08/02/2024]
Abstract
Amyloidosis is a complex group of rare disorders characterized by the deposition of misfolded proteins in the extracellular space of various tissues and organs, leading to progressive organ dysfunction. The kidneys constitute a very common site affected, most notably by immunoglobulin-mediated (light chain, heavy chain, and light and heavy chain amyloidosis), but other types that include serum amyloid A (AA) amyloidosis and leukocyte chemotactic factor 2 amyloidosis, along with mutant proteins in several hereditary forms of amyloidosis such as transthyretin, fibrinogen α-chain, gelsolin, lysozyme, and apolipoproteins AI/AII/AIV/CII/CIII amyloidosis have been incriminated as well. The clinical presentation is variable and can range from minimal proteinuria for leukocyte chemotactic factor 2 amyloidosis to a full-blown nephrotic syndrome for AA amyloidosis. Clinical correlation, genetic analysis, and adequate tissue typing through a kidney biopsy are essential to make the correct diagnosis, especially when a family history of amyloidosis is absent. Except for AA and transthyretin amyloidosis, the treatment is usually purely supportive. Kidney transplantation is an acceptable form of treatment for end-stage kidney disease in all types of non-Ig-mediated renal amyloidosis.
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Affiliation(s)
- Sabine Karam
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis.
| | - Amit Kaushal
- Division of Nephrology, West Virginia University, Morgantown, WV
| | - Nabil Abu Amer
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Virginie Royal
- Division of Pathology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Canada
| | - Abhijat KItchlu
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
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Ozdag Y, Koshinski JL, Carry BJ, Gardner JM, Garcia VC, Dwyer CL, Akoon A, Klena JC, Grandizio LC. A Comparison of Amyloid Deposition in Endoscopic and Open Carpal Tunnel Release. J Hand Surg Am 2024; 49:301-309. [PMID: 38363261 DOI: 10.1016/j.jhsa.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/27/2023] [Accepted: 01/09/2024] [Indexed: 02/17/2024]
Abstract
PURPOSE Previous investigations assessing the incidence of amyloidosis detected with biopsy during carpal tunnel release (CTR) have focused on open CTR (OCTR). Prior authors have suggested that biopsy may be more technically challenging during endoscopic carpal tunnel release (ECTR). Our purpose was to compare differences in the incidence of amyloid deposition detected during ECTR versus OCTR. METHODS We reviewed all primary ECTR and OCTR during which a biopsy for amyloid was obtained between February 2022 and June 2023. All procedures were performed by five upper-extremity surgeons from a single institution. Congo red staining was used to determine the presence of amyloid deposition in either the transverse carpal ligament (TCL) or tenosynovium. All positive cases underwent subtype analysis and protein identification through liquid chromatography-tandem mass spectrometry. Baseline demographics were recorded for each case, and the incidence of positive biopsy was compared between ECTR and OCTR cases. RESULTS A total of 282 cases were included for analysis (143 ECTR and 139 OCTR). The mean age was 67 years, and 45% of cases were women. Baseline demographics were similar except for a significantly higher incidence of diabetes in OCTR cases (13% vs 33%). Overall, 13% of CTR cases had a positive biopsy. There was a statistically significant difference in the incidence of amyloid deposition detected during biopsy in ECTR cases (3.5%) compared with OCTR cases (23%). CONCLUSIONS Biopsy performed during ECTR may result in a lower incidence of amyloid detection. Future basic science investigation may be necessary to determine histologic differences between tenosynovium proximal and distal to the leading edge of the TCL. When surgeons plan a biopsy during surgical release of the carpal tunnel, an open approach may be advantageous. TYPE OF STUDY/LEVEL OF EVIDENCE Prognostic II.
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Affiliation(s)
- Yagiz Ozdag
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - Jessica L Koshinski
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - Brendan J Carry
- Department of Cardiology, Heart Institute, Geisinger Health System, Danville, PA
| | - Jerad M Gardner
- Departments of Laboratory Medicine and Dermatology, Geisinger Health System, Danville, PA
| | - Victoria C Garcia
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - C Liam Dwyer
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - Anil Akoon
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - Joel C Klena
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA
| | - Louis C Grandizio
- Department of Orthopaedic Surgery, Geisinger Musculoskeletal Institute, Geisinger Commonwealth School of Medicine, Danville, PA.
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Huart A. Birtamimab: a new amyloidosis treatment? Blood 2023; 142:1178-1180. [PMID: 37796521 DOI: 10.1182/blood.2023021311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023] Open
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Foster JS, Balachandran M, Hancock TJ, Martin EB, Macy S, Wooliver C, Richey T, Stuckey A, Williams AD, Jackson JW, Kennel SJ, Wall JS. Development and characterization of a prototypic pan-amyloid clearing agent - a novel murine peptide-immunoglobulin fusion. Front Immunol 2023; 14:1275372. [PMID: 37854603 PMCID: PMC10580800 DOI: 10.3389/fimmu.2023.1275372] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 09/13/2023] [Indexed: 10/20/2023] Open
Abstract
Introduction Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid. Methods The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum. Results Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9. Conclusion Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jonathan S. Wall
- Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, United States
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Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J 2023; 480:1217-1240. [PMID: 37584410 DOI: 10.1042/bcj20230241] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as 'self', and otherwise immunologically silent. The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies. A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.
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Affiliation(s)
- Douglas B Kell
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, 2800 Kgs Lyngby, Denmark
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
| | - Etheresia Pretorius
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
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Tsoi MR, Lin JH, Patel AR. Emerging Therapies for Transthyretin Amyloidosis. Curr Oncol Rep 2023; 25:549-558. [PMID: 36943555 DOI: 10.1007/s11912-023-01397-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/23/2023]
Abstract
PURPOSE OF REVIEW This review provides an overview of the available therapies for treating neuropathic and/or cardiac manifestations of transthyretin amyloidosis (ATTR), as well as investigational therapeutic agents in ongoing clinical trials. We discuss additional emergent approaches towards thwarting this life-threatening disease that until recently was considered virtually untreatable. RECENT FINDINGS Advances in noninvasive diagnostic methods for detecting ATTR have facilitated easier diagnosis and detection at an earlier stage of disease when therapeutic interventions are likely to be more effective. There are now several ATTR-directed treatments that are clinically available, as well as investigational agents that are being studied in clinical trials. Therapeutic strategies include tetramer stabilization, gene silencing, and fibril disruption. ATTR has been historically underdiagnosed. With advances in diagnostic methods and the advent of disease-modifying treatments, early diagnosis and initiation of treatment is revolutionizing management of this disease.
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Affiliation(s)
- Melissa R Tsoi
- Department of Medicine, Tufts Medical Center, MA, 02111, Boston, USA
| | - Jeffrey H Lin
- Department of Medicine, Tufts Medical Center, MA, 02111, Boston, USA
| | - Ayan R Patel
- Cardiac Amyloidosis Program, Tufts Medical Center, 800 Washington St., MA, 02111, Boston, USA.
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Mahadevia H, Ponvilawan B, Sharma P, Al-Obaidi A, Qasim H, Koyi J, Anwer F, Raza S. Advancements and future trends of immunotherapy in light-chain amyloidosis. Crit Rev Oncol Hematol 2023; 183:103917. [PMID: 36696931 DOI: 10.1016/j.critrevonc.2023.103917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/05/2022] [Accepted: 01/20/2023] [Indexed: 01/23/2023] Open
Abstract
Light-chain (AL) amyloidosis is a type of plasma cell neoplasm with abnormal monoclonal immunoglobulin light-chain production and their subsequent deposition in tissues causing end-organ damage. In addition to existing treatments including autologous stem cell transplantation, there is a need for other approaches for eradicating abnormal plasma cells and amyloid tissue deposits. Treatment strategies of AL amyloidosis are mostly based on medications that are effective in multiple myeloma due to similar cell of origin. Daratumumab along with proteasome inhibitors and corticosteroids has become standard of care for AL amyloidosis. Another appealing approach is disassembling amyloid deposits with hope to potentially reverse the damage done by the disease. This was met with promising results for CAEL-101 and birtamimab. Although still in early stages, novel treatment options in pipeline, including antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell therapy may diversify the treatment armamentarium of AL amyloidosis in the future.
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Affiliation(s)
- Himil Mahadevia
- Department of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Ben Ponvilawan
- Department of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Parth Sharma
- Department of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Ammar Al-Obaidi
- Department of Hematology/Oncology, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Hana Qasim
- Department of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Jagadish Koyi
- Department of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes St, Kansas City, MO 64108, USA.
| | - Faiz Anwer
- Taussig Cancer Center, Cleveland Clinic, 10201 Carnegie Ave, Cleveland, OH 44106, USA.
| | - Shahzad Raza
- Taussig Cancer Center, Cleveland Clinic, 10201 Carnegie Ave, Cleveland, OH 44106, USA.
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Wechalekar AD, Cibeira MT, Gibbs SD, Jaccard A, Kumar S, Merlini G, Palladini G, Sanchorawala V, Schönland S, Venner C, Boccadoro M, Kastritis E. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group. Amyloid 2023; 30:3-17. [PMID: 35838162 DOI: 10.1080/13506129.2022.2093635] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND This guideline has been developed jointly by the European Society of Haematology and International Society of Amyloidosis recommending non-transplant chemotherapy treatment for patients with AL amyloidosis. METHODS A review of literature and grading of evidence as well as expert recommendations by the ESH and ISA guideline committees. RESULTS AND CONCLUSIONS The recommendations of this committee suggest that treatment follows the clinical presentation which determines treatment tolerance tempered by potential side effects to select and modify use of drugs in AL amyloidosis. All patients with AL amyloidosis should be considered for clinical trials where available. Daratumumab-VCD is recommended from most untreated patients (VCD or VMDex if daratumumab is unavailable). At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients' fitness/frailty and end organ damage. Targeted agents like venetoclax need urgent prospective evaluation. Future prospective trials should include advanced stage patients to allow for evidence-based treatment decisions. Therapies targeting amyloid fibrils or those reducing the proteotoxicity of amyloidogenic light chains/oligomers are urgently needed.
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Affiliation(s)
- Ashutosh D Wechalekar
- National Amyloidosis Centre, University College London (Royal Free Campus), London, UK
| | - M Teresa Cibeira
- Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain
| | - Simon D Gibbs
- Victorian and Tasmanian Amyloidosis Service, Eastern Health Monash University Clinical School, Box Hill, VIC, Australia
| | - Arnaud Jaccard
- Hematology Department, French Reference Center for AL Amyloidosis (Limoges-Poitiers), CHU Limoges, Limoges, France
| | - Shaji Kumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo" and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Giovanni Palladini
- Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo" and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Vaishali Sanchorawala
- Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Stefan Schönland
- Medical Department V, Amyloidosis Center, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Mario Boccadoro
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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Abstract
Systemic light chain (AL) amyloidosis is caused by an usually small B cell clone that produces a toxic light chain forming amyloid deposits in tissue. The heart and kidney are the major organs affected, but all others, with the exception of the CNS, can be involved. The disease is rapidly progressive, and it is still diagnosed late. Screening programs in patients followed by hematologists for plasma cell dyscrasias should be considered. The diagnosis requires demonstration in a tissue biopsy of amyloid deposits formed by immunoglobulin light chains. The workup of patients with AL amyloidosis requires adequate technology and expertise, and patients should be referred to specialized centers whenever possible. Stagings are based on cardiac and renal biomarkers and guides the choice of treatment. The combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (dara-CyBorD) is the current standard of care. Autologous stem cell transplant is performed in eligible patients, especially those who do not attain a satisfactory response to dara-CyBorD. Passive immunotherapy targeting the amyloid deposits combined with chemo-/immune-therapy targeting the amyloid clone is currently being tested in controlled clinical trials. Response to therapy is assessed based on validated criteria. Profound hematologic response is the early goal of treatment and should be accompanied over time by deepening organ response. Many relapsed/refractory patients are also treated with daratumumab combination, but novel regimens will be needed to rescue daratumumab-exposed subjects. Immunomodulatory drugs are the current cornerstone of rescue therapy, while immunotherapy targeting B-cell maturation antigen and inhibitors of Bcl-2 are promising alternatives.
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Current Understanding of Systemic Amyloidosis and Underlying Disease Mechanisms. Am J Cardiol 2022; 185 Suppl 1:S2-S10. [PMID: 36549788 DOI: 10.1016/j.amjcard.2022.10.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 12/24/2022]
Abstract
Amyloidosis is a group of diverse disorders caused by misfolded proteins that aggregate into insoluble fibrils and ultimately cause organ damage. In medical practice, amyloidosis classification is based on the amyloid precursor protein type, of which amyloid immunoglobulin light chain, amyloid transthyretin, amyloid leukocyte chemotactic factor 2, and amyloid derived from serum amyloid A protein are the most common. Distinct mechanisms appear to be predominantly operational in the pathogenesis of particular types of amyloidosis, including increased protein precursor synthesis, somatic or germ line mutations, and inherent instability in the precursor protein in its wild form. An increased supply of misfolded proteins and/or a decreased capacity of the protein quality control systems can result in an imbalance that leads to increased circulation of misfolded proteins. Although the detection of mature fibrils is the basis for diagnosis of amyloidosis, a growing body of evidence has implicated the prefibrillar species as proteotoxic and key contributors to the development of the disease.
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Abstract
Systemic amyloidoses are characterized by the unrelenting deposition of autologous proteins as highly ordered fibrils in target organs. The ensuing, potentially fatal organ dysfunction is the result of the combined damage caused by the proteotoxic effect of prefibrillar species and by the cytotoxicity and the structural alterations produced by the amyloid fibrils. Current therapy is focused on eliminating the amyloid protein, thus extinguishing the amyloid cascade at its origin. While this approach may end the cell damage caused by prefibrillar aggregates and prevent further amyloid accumulation, the noxious effects of the amyloid fibrils persist and may hamper the recovery of organ function, which is the ultimate goal of therapy as it is necessary to improve the quality of life and extend survival. Preclinical studies indicate that the clearance of amyloid deposits can be accelerated by specific antibodies targeting amyloid fibrils that activate complement-mediated macrophages and giant cell phagocytosis, possibly promoting the recovery of organ function. Measuring the therapeutic effect of anti-amyloid agents is still a matter of research. In recent years, several monoclonal antibodies targeting amyloid deposits have been tested in clinical trials with mixed outcomes. Recent encouraging results from phase I/II trials, new anti-amyloid agents, and new antibody engineering offer hope that effective amyloid removal will be accomplished in the near future, accelerating organ recovery and improving quality of life and survival.
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Kim C, Simon B, Vaidya N, Kirk S, Estes K, Ghadiali L, Kontosis A, Yoo D. Contrasting presentations of the same disease: A comparison of two cases of amyloidosis presenting with eyelid involvement. Am J Ophthalmol Case Rep 2022; 28:101714. [PMID: 36217437 PMCID: PMC9547226 DOI: 10.1016/j.ajoc.2022.101714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 07/26/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Purpose Localized amyloidosis can affect numerous tissues throughout the body and can also affect a variety of peri-ocular tissues including the conjunctiva, extra-ocular muscles, peri-orbital soft tissue, and lacrimal gland. We report two cases of amyloidosis presenting with eyelid involvement. Observations The first case represented a more subtle presentation of skin thickening with a pre-septal cellulitis, while the second case had a dramatic presentation of edema evolving into tissue dehiscence and spontaneous hemorrhage with ongoing angioedema and systemic coagulopathy. Conclusions and importance The two cases of biopsy-proven orbital/peri-ocular amyloidosis demonstrate the different clinical presentations that may go from the subtle to dramatic, depending on which peri-ocular tissues are affected and to what degree. Standards for treatment of amyloidosis remain conservative initially with surgery or radiation recommended only for refractory cases, but additional therapies are under investigation. Clinicians should have high clinical suspicion for amyloidosis with findings such as skin thickening or significant periorbital edema and should always consider tissue biopsy and further workup for amyloidosis if the findings worsen or do not resolve with treatment of more common conditions such as cellulitis.
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Affiliation(s)
- Christian Kim
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
- Corresponding author.
| | - Brian Simon
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - Neel Vaidya
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - Suzanne Kirk
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - Kimberly Estes
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - Larissa Ghadiali
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - Andreas Kontosis
- Loyola University Medical Center Department of Pathology, Building 2160 S. First Avenue, Maywood, IL, 60153, United States
| | - David Yoo
- Loyola University Medical Center Department of Ophthalmology, Building 102/Room 2605, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, United States
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Richards D, Millns H, Cookson L, Lukas MA. An observational, non-interventional study for the follow-up of patients with amyloidosis who received miridesap followed by dezamizumab in a phase 1 study. Orphanet J Rare Dis 2022; 17:259. [PMID: 35810311 PMCID: PMC9271258 DOI: 10.1186/s13023-022-02405-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 06/26/2022] [Indexed: 11/10/2022] Open
Abstract
Background Miridesap depletes circulating serum amyloid P (SAP) and dezamizumab (anti-SAP monoclonal antibody) targets SAP on amyloid deposits, triggering amyloid removal. In a phase 1, first-in-human study (FIHS), progressive amyloid removal was observed in some patients after ≤ 3 cycles of miridesap/dezamizumab. Methods This observational, non-interventional study in patients who received miridesap/dezamizumab during the FIHS (planned follow-up: 5 years) evaluated response to treatment based on routine assessments of disease status and key organ function. In a post hoc analysis, patients responding to treatment in the FIHS during follow-up were identified as responders and further categorized as sustained or declining responders.
Results In the FIHS, 17/23 patients were treatment responders. Of these patients, seven (immunoglobulin light chain [AL], n = 6; serum amyloid A, n = 1) were considered sustained responders and ten (fibrinogen-a alpha chain [AFib], n = 5; AL, n = 4; apolipoprotein A-I, n = 1) were considered declining responders. We primarily present responder patient-level data for functional, cardiac, laboratory and imaging assessments conducted during the follow-up period, with non-responder data presented as supplementary. Conclusion No further development of miridesap/dezamizumab is planned in amyloidosis. However, long-term follow-up of these patients may provide insight into whether active removal of amyloid deposits has an impact on disease progression. Trial registration ClinicalTrials.gov, NCT01777243. Registered 28 January 2013, https://clinicaltrials.gov/ct2/show/study/NCT01777243. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02405-7.
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