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Pharmacological Research Mar 2024Since its discovery in 1998, the use of small interfering RNA (siRNA) has been increasing in biomedical studies because of its ability to very selectively inhibit the... (Review)
Review
Since its discovery in 1998, the use of small interfering RNA (siRNA) has been increasing in biomedical studies because of its ability to very selectively inhibit the expression of any target gene. Thus, siRNAs can be used to generate therapeutic compounds for different diseases, including those that are currently 'undruggable'. This has led siRNA-based therapeutic compounds to break into clinical settings, with them holding the promise to potentially revolutionise therapeutic approaches. To date, the United States Food and Drug Administration (FDA) have approved 5 compounds for treating different diseases including hypercholesterolemia, transthyretin-mediated amyloidosis (which leads to polyneuropathy), hepatic porphyria, and hyperoxaluria. This current article presents an overview of the molecular mechanisms involved in the selective pharmacological actions of siRNA-based compounds. It also describes the ongoing clinical trials of siRNA-based therapeutic compounds for hepatic diseases, pulmonary diseases, atherosclerosis, hypertriglyceridemia, transthyretin-mediated amyloidosis, and hyperoxaluria, kidney diseases, and haemophilia, as well as providing a description of FDA-approved siRNA therapies. Because of space constraints and to provide an otherwise comprehensive review, siRNA-based compounds applied to cancer therapies have been excluded. Finally, we discuss how the use of lipid-based nanoparticles to deliver siRNAs holds promise for selectively targeting mRNA-encoding proteins associated with the genesis of different diseases. Thus, siRNAs can help reduce the cellular levels of these proteins, thereby contributing to disease treatment. As consequence, a marked increase in the number of marketed siRNA-based medicines is expected in the next two decades, which will likely open up a new era of therapeutics.
Topics: United States; Humans; RNA, Small Interfering; Prealbumin; Nanoparticles; Amyloid Neuropathies, Familial; Hyperoxaluria
PubMed: 38331236
DOI: 10.1016/j.phrs.2024.107102 -
Revista Espanola de Cardiologia... May 2024
Topics: Humans; Amyloid Neuropathies, Familial; Diflunisal; Male; Cardiomyopathies; Female; Aged; Treatment Outcome; Middle Aged
PubMed: 38325700
DOI: 10.1016/j.rec.2023.10.016 -
Journal of the American Heart... Feb 2024Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing...
BACKGROUND
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis.
METHODS AND RESULTS
This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; =0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; =0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; =0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; =0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; <0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; <0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; =0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; =0.01).
CONCLUSIONS
Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.
Topics: Humans; Prealbumin; Cardiomyopathies; Amyloid Neuropathies, Familial; Stroke Volume; Retrospective Studies; Alkaline Phosphatase; Hyponatremia; Ventricular Function, Left; Prognosis; Biomarkers; Anemia; Hyperbilirubinemia; Urea
PubMed: 38314569
DOI: 10.1161/JAHA.123.033094 -
CMAJ : Canadian Medical Association... Jan 2024
Topics: Humans; Amyloid Neuropathies, Familial; Carpal Tunnel Syndrome
PubMed: 38286493
DOI: 10.1503/cmaj.230671 -
ESC Heart Failure Apr 2024The early diagnosis of cardiac amyloidosis (CA) is paramount, since there are effective therapies that improve patient survival. The diagnostic accuracy of classical...
AIMS
The early diagnosis of cardiac amyloidosis (CA) is paramount, since there are effective therapies that improve patient survival. The diagnostic accuracy of classical electrocardiographic (ECG) signs, such as low voltage, pseudoinfarct pattern, and conduction disturbances in the diagnosis of CA, is inferior to that of the echocardiographic myocardial deformation criteria; therefore, our aim was to find more accurate novel ECG criteria for this purpose.
METHODS
We tested the diagnostic value of five novel ECG criteria, two of them devised by us, in 34 patients with confirmed CA (20 transthyretin amyloidosis and 14 AL amyloidosis) and 45 control patients with left ventricular hypertrophy on echocardiography due to hypertension, valvular aortic stenosis and hypertrophic cardiomyopathy. The following novel ECG criteria, that suggested CA, were tested: QRS amplitude in lead I < 0.55 mV (I < 0.55); QRS amplitude in lead aVR < 0.5 mV (aVR < 0.5); average QRS amplitude of leads I + aVR < 0.575 mV [(I + aVR) < 0.575]; average QRS amplitude of leads I + aVR/average QRS amplitude of leads V < 0.375 [(I + aVR)/(V) < 0.375]; average QRS amplitude of leads I + aVR/longest intrinsicoid deflection in leads I,aVL,V < 0.0115 [(I + aVR)/I,aVL,VID < 0.0115].
RESULTS
The I < 0.55, aVR < 0.5, (I + aVR) < 0.575, (I + aVR)/(V) < 0.375, (I + aVR)/I,aVL,VID < 0.0115 test accuracy (TA) were 81%, 84.8%, 82.3%, 84.8%, and 83.3%, respectively; the sensitivity (SE): 76.5%, 82.4%, 85.3%, 82.4%, and 76.9%; specificity (SP): 84.4%, 86.7%, 80%, 86.7%, and 87.5%; positive predictive values (PPV): 78.8%, 82.4%, 76.3%, 82.4%, and 80%; negative predictive values (NPV): 82.6%, 86.7%, 87.8%, 86.7%, and 85.4%; area under curve (AUC) values: 0.8922, 0.8794, 09016, 0.8824, and 0.8462 were respectively. These parameters of the novel ECG criteria were at least as good as those reported by other authors in the literature of the qualitative (TA: 67%, SE: 80%, SP: 34%, PPV: 75%, NPV: 42%, AUC: 0.57) and quantitative apical sparing (TA: 64-80%, SE: 66-81.3%, SP: 55-78.3%, PPV: 33-83.9%, NPV: 41-75%, AUC: 0.62-0.68) and left ventricular ejection fraction/global longitudinal strain >4.1 (TA: 77%, SE: 93%, SP: 38%, PPV: 79%, NPV: 69%, AUC: 0.65) echocardiographic criteria. Among the classical criteria, the low voltage in limb leads criterion was present most frequently (in 73.5%) in patients with CA, with slightly worse diagnostic value than the novel ECG criteria (TA: 78.5%, SE: 73.5%, SP: 82.2%, PPV: 75.8%, NPV: 80.4%).
CONCLUSIONS
The novel ECG criteria [mostly the aVR < 0.5, (I + aVR)/(V) < 0.375] seem at least as reliable in the diagnosis of CA as the best echocardiographic myocardial deformation criteria and might be used either together with the echocardiographic criteria or as stand-alone criteria to diagnose CA in the future.
Topics: Humans; Stroke Volume; Ventricular Function, Left; Electrocardiography; Echocardiography; Amyloid Neuropathies, Familial
PubMed: 38243379
DOI: 10.1002/ehf2.14655 -
PloS One 2024Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multi-systemic disease with wild-type (ATTRwt) and hereditary (ATTRv) forms. Over 130 variants associated... (Observational Study)
Observational Study
Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multi-systemic disease with wild-type (ATTRwt) and hereditary (ATTRv) forms. Over 130 variants associated with ATTRv amyloidosis have been identified, although little is known about the majority of these genotypes. This analysis examined phenotypic characteristics of symptomatic patients with ATTRv amyloidosis enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS) with four less frequently reported pathogenic genotypes: F64L (c.250T>C, p.F84L), I68L (c.262A>T, p.I88L), I107V (c.379A>G; p.I127V), and S77Y (c.290C>A; p.S97Y). THAOS is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both ATTRwt and ATTRv amyloidosis. This analysis describes the baseline demographic and clinical characteristics of untreated symptomatic patients with the F64L, I68L, I107V, or S77Y genotypes at enrollment in THAOS (data cutoff date: January 4, 2022). There were 141 symptomatic patients with F64L (n = 46), I68L (n = 45), I107V (n = 21), or S77Y (n = 29) variants at the data cutoff. Most patients were male and median age at enrollment was in the sixth decade for S77Y patients and the seventh decade for the others. A predominantly neurologic phenotype was associated with F64L, I107V, and S77Y genotypes, whereas patients with the I68L genotype presented with more pronounced cardiac involvement. However, a mixed phenotype was also reported in a considerable proportion of patients in each variant subgroup. This analysis from THAOS represents the largest study of ATTRv symptomatic patients with the F64L, I68L, I107V, and S77Y genotypes. These data add to the limited knowledge on the clinical profile of patients with specific ATTRv variants and emphasize the importance of comprehensive assessment of all patients. Trial registration ClinicalTrials.gov: NCT00628745.
Topics: Female; Humans; Male; Amyloid Neuropathies, Familial; Genotype; Phenotype; Prealbumin; Surveys and Questionnaires; Middle Aged; Aged
PubMed: 38241252
DOI: 10.1371/journal.pone.0292435 -
Heart Failure Reviews Mar 2024Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial... (Review)
Review
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial deposition. The development of wild-type TTR amyloid fibrils is a complex pathological process linked to the deterioration of homeostatic mechanisms owing to aging, plausibly implicating multiple molecular mechanisms. The components of amyloid transthyretin often include serum amyloid P, proteoglycans, and clusterin, which may play essential roles in the localization and elimination of amyloid fibrils. Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment. Recently, tafamidis has been the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTRwt-CM. In addition, small interfering RNAs and antisense oligonucleotides for ATTR-CM are promising therapeutic approaches and are currently in phase III clinical trials. Newly emerging therapies, such as antibodies targeting amyloid, inhibitors of seed formation, and CRISPR‒Cas9 technology, are currently in the early stages of research. The development of novel therapies is based on progress in comprehending the molecular events behind amyloid cardiomyopathy. There is still a need to further advance innovative treatments, providing patients with access to alternative and effective therapies, especially for patients diagnosed at a late stage.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Heart Failure; Myocardium; Cardiomyopathies
PubMed: 38233673
DOI: 10.1007/s10741-023-10380-9 -
Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy.Nature Communications Jan 2024ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic...
ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.
Topics: Humans; Amyloid; Amyloid Neuropathies, Familial; Cryoelectron Microscopy; Prealbumin; Heart; Brain Diseases
PubMed: 38233397
DOI: 10.1038/s41467-024-44820-3 -
Revista Espanola de Cardiologia... Jun 2024
Topics: Humans; Amyloid Neuropathies, Familial; Male; Female; Middle Aged; Aged; Mass Screening; Adult; Spain; Prealbumin; Genetic Testing
PubMed: 38220055
DOI: 10.1016/j.rec.2023.12.006