-
BioDrugs : Clinical Immunotherapeutics,... Sep 2022The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues... (Review)
Review
The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.
Topics: Acetylgalactosamine; Humans; Prealbumin; RNA Interference; RNA, Small Interfering
PubMed: 35997897
DOI: 10.1007/s40259-022-00549-3 -
The New England Journal of Medicine Aug 2021Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein...
BACKGROUND
Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting .
METHODS
After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study.
RESULTS
Preclinical studies showed durable knockout of after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.
CONCLUSIONS
In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of . (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
Topics: Amyloid Neuropathies, Familial; CRISPR-Cas Systems; Female; Gene Editing; Gene Transfer Techniques; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Nanoparticles; Prealbumin; RNA, Guide, CRISPR-Cas Systems; RNA, Messenger
PubMed: 34215024
DOI: 10.1056/NEJMoa2107454 -
Methodist DeBakey Cardiovascular Journal 2022Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted... (Review)
Review
Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA). The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene ( silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Prealbumin; Transplantation, Autologous
PubMed: 35414852
DOI: 10.14797/mdcvj.1050 -
Methodist DeBakey Cardiovascular Journal 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease and an underestimated cause of both heart failure and conduction abnormalities. It is... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease and an underestimated cause of both heart failure and conduction abnormalities. It is characterized by pathologic accumulation of extracellular protein arising from unstable transthyretin (TTR) tetramers, which dissociate into monomers that misfold, aggregate, and form insoluble fibrils that are resistant to proteolysis. Cardiac amyloidosis appears in two distinct forms: hereditary and wild-type. There is considerable heterogeneity in the clinical presentation of ATTR, ranging from primarily cardiac, primarily neuropathic, or mixed cardiac and neuropathic disease. Pathogenic variants in the gene that predominantly involve the heart include Val122Ile, Leu111Met, and Ile68Leu. The wild-type form of ATTR is also predominantly cardiac. Phenotypic heterogeneity is linked to differences among specific pathogenic variants, geography, and the subtype of endemic versus nonendemic disease. Factors contributing to wild-type ATTR are largely unknown, but similar factors likely influence the penetrance of hereditary ATTR. Recognition of ATTR-CM is improving due to the increased use of cardiac scintigraphy as a noninvasive diagnostic tool, and early recognition of cardiac infiltration is crucial to optimize long-term prognosis.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans; Prealbumin; Prognosis
PubMed: 35414855
DOI: 10.14797/mdcvj.1066 -
Neurochemistry International May 2022Transthyretin (TTR), which is one of the major amyloidogenic proteins in systemic amyloidosis, forms extracellular amyloid deposits in the systemic organs such as... (Review)
Review
Transthyretin (TTR), which is one of the major amyloidogenic proteins in systemic amyloidosis, forms extracellular amyloid deposits in the systemic organs such as nerves, ligaments, heart, and arterioles, and causes two kinds of systemic amyloidosis, hereditary ATTR (ATTRv) amyloidosis induced by variant TTR and aging-related wild-type ATTR (ATTRwt) amyloidosis. More than 150 different mutations, most of which are amyloidogenic, have been reported in the TTR gene. Since most disease-associated mutations affect TTR tetramer dissociation rates, destabilization of TTR tetramers is widely believed to be a critical step in TTR amyloid formation. Recently, effective disease-modifying therapies such as TTR tetramer stabilizers and TTR gene silencing therapies have been developed for ATTR amyloidosis. This study reviews the clinical phenotypes of ATTR amyloidosis, TTR features, and recent progress in promising therapies for ATTR amyloidosis.
Topics: Amyloid; Amyloidogenic Proteins; Amyloidosis; Humans; Mutation; Prealbumin
PubMed: 35218869
DOI: 10.1016/j.neuint.2022.105313 -
European Journal of Heart Failure Jun 2021Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR-CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR-CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best-practice guidance. In this report, experts with experience in treating amyloidosis and ATTR-CM developed consensus recommendations for monitoring the course of patients with ATTR-CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR-CM will help to elucidate, refine and define these and other measurements.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Consensus; Heart Failure; Humans; Prealbumin
PubMed: 33915002
DOI: 10.1002/ejhf.2198 -
JAMA Mar 2024Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy. (Review)
Review
IMPORTANCE
Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy.
OBSERVATIONS
Transthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course.
CONCLUSIONS AND RELEVANCE
ATTR amyloidosis causes cardiomyopathy in up to approximately 150 000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart Failure; Immunoglobulin Light-chain Amyloidosis; Prealbumin; Black or African American; United States; Africa, Western; Protein Folding
PubMed: 38441582
DOI: 10.1001/jama.2024.0442 -
Nucleic Acids Research Dec 2020One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species...
One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly generated Argonaute 2 protein complexes weeks after dosing, enabling continuous RNAi activity over time. Identical siRNAs delivered in lipid nanoparticles or as GalNAc conjugates were dose-adjusted to achieve similar knockdown, but only GalNAc-siRNAs supported an extended duration of activity, illustrating the importance of receptor-mediated siRNA trafficking in the process. Taken together, we provide several lines of evidence that acidic intracellular compartments serve as a long-term depot for GalNAc-siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo.
Topics: Acetylgalactosamine; Animals; Argonaute Proteins; Asialoglycoprotein Receptor; Biological Transport; Drug Carriers; Drug Stability; Female; Gene Silencing; Glycoconjugates; Hepatocytes; Humans; Hydrogen-Ion Concentration; Liver; Mice; Mice, Inbred C57BL; Nanoparticles; Prealbumin; RNA, Small Interfering; Time Factors
PubMed: 32808038
DOI: 10.1093/nar/gkaa670 -
Circulation Jul 2020Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.
Topics: Algorithms; Alleles; Amyloidosis; Animals; Biomarkers; Cardiomyopathies; Clinical Decision-Making; Disease Management; Disease Susceptibility; Gene Silencing; Genetic Predisposition to Disease; Genotype; Heart Function Tests; Humans; Magnetic Resonance Imaging; Molecular Diagnostic Techniques; Prealbumin
PubMed: 32476490
DOI: 10.1161/CIR.0000000000000792 -
ESC Heart Failure Dec 2019Transthyretin cardiac amyloidosis (ATTR-CA) demonstrates progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of... (Review)
Review
Transthyretin cardiac amyloidosis (ATTR-CA) demonstrates progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of transthyretin-derived insoluble amyloid fibrils in the myocardium. Two distinct types of transthyretin (wild type or variant) become unstable, and misfolding forms aggregate, resulting in amyloid fibrils. ATTR-CA, which has previously been underrecognized and considered to be rare, has been increasingly recognized as a cause of heart failure with preserved ejection fraction among elderly persons. With the advanced technology, the diagnostic tools have been improving for cardiac amyloidosis. Recently, the efficacy of several disease-modifying agents focusing on the amyloidogenic process has been demonstrated. ATTR-CA has been changing from incurable to treatable. Nevertheless, there are still no prognostic improvements due to diagnostic delay or misdiagnosis because of phenotypic heterogeneity and co-morbidities. Thus, it is crucial for clinicians to be aware of this clinical entity for early diagnosis and proper treatment. In this mini-review, we focus on recent advances in diagnosis and treatment of ATTR-CA.
Topics: Aged; Amyloid; Amyloidosis; Cardiomyopathies; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Myocardium; Prealbumin
PubMed: 31553132
DOI: 10.1002/ehf2.12518