Abstract
Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T4) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.
Keywords: Transthyretin (TTR), amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), protein misfolding, native state kinetic stabilization, diflunisal
Current Pharmaceutical Design
Title: Pathogenesis of and Therapeutic Strategies to Ameliorate the Transthyretin Amyloidoses
Volume: 14 Issue: 30
Author(s): Yoshiki Sekijima, Jeffery W. Kelly and Shu-ichi Ikeda
Affiliation:
Keywords: Transthyretin (TTR), amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), protein misfolding, native state kinetic stabilization, diflunisal
Abstract: Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T4) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.
Export Options
About this article
Cite this article as:
Sekijima Yoshiki, Kelly W. Jeffery and Ikeda Shu-ichi, Pathogenesis of and Therapeutic Strategies to Ameliorate the Transthyretin Amyloidoses, Current Pharmaceutical Design 2008; 14 (30) . https://dx.doi.org/10.2174/138161208786404155
DOI https://dx.doi.org/10.2174/138161208786404155 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
FoxO1 Inhibitors: The Future Medicine for Metabolic Disorders?
Current Diabetes Reviews Antibodies Against G-Protein Coupled Receptors: Novel Uses in Screening and Drug Development
Combinatorial Chemistry & High Throughput Screening Inflammation and Chronic Heart Failure: From Biomarkers to Novel Anti-inflammatory Therapeutic Strategies
Medicinal Chemistry The Impact of Methodology and Confounding Variables on the Association Between Major Depression and Coronary Heart Disease: Review and Recommendations
Current Psychiatry Reviews The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research
Current Drug Targets Regression of Oxidative Stress by Targeting eNOS and Nrf2/ARE Signaling: A Guided Drug Target for Cardiovascular Diseases
Current Topics in Medicinal Chemistry Recent Patents on Oxidative Stress-Related Biomarkers in Chronic Heart Failure: The Central Role of Endothelium and Myeloperoxidase
Recent Patents on Biomarkers Autophagy and Mitochondria in Obesity and Type 2 Diabetes
Current Diabetes Reviews The Role of Mitochondrial Dysfunction in Heart Failure and Potential Therapeutic Targets
Current Pharmaceutical Design Conventional and Non-Conventional Targets of Natural Products in the Management of Diabetes Mellitus and Associated Complications
Current Medicinal Chemistry Withdrawal Notice: COVID-19: Outbreak to Global
Anti-Infective Agents Targeting Apelinergic System in Cardiometabolic Disease
Current Drug Targets Natural Products for Fungal Diseases Management and Prevention
The Natural Products Journal Stem Cells: Clinical Trials Results The End of the Beginning or the Beginning of the End?
Cardiovascular & Hematological Disorders-Drug Targets Stem Cell-Based Immunomodulation in Type 1 Diabetes: Beyond the Regenerative Approach
Current Pharmaceutical Design Anthracycline-Induced Cardiotoxicity
Cardiovascular & Hematological Agents in Medicinal Chemistry Selenium Deficiency in Soils and Crops and its Impact on Animal and Human Health
Current Nutrition & Food Science QT Alterations in Psychopharmacology: Proven Candidates and Suspects
Current Drug Safety Biomarkers Associated with Bleeding Risk in the Setting of Atrial Fibrillation
Current Medicinal Chemistry Endothelial Dysfunction in the Hypertensive State: Mechanisms of Hypertensive Cardiovascular Complications
Current Hypertension Reviews