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1.
Pharmacol Rev ; 72(4): 862-898, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929000

RESUMO

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.


Assuntos
RNA/efeitos dos fármacos , RNA/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/uso terapêutico , Betacoronavirus , Técnicas de Química Analítica/métodos , Técnicas de Química Analítica/normas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/organização & administração , Descoberta de Drogas , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA/efeitos adversos , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , RNA Guia/farmacologia , RNA Guia/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/farmacologia , RNA Ribossômico/efeitos dos fármacos , RNA Ribossômico/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , RNA Viral/efeitos dos fármacos , Ribonucleases/metabolismo , Riboswitch/efeitos dos fármacos
2.
Hum Cell ; 33(4): 1186-1196, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700262

RESUMO

Pancreatic cancer is the fourth most common lethal malignancy with an overall 5-year survival rate of less than 5%. ERas, a novel Ras family member, was first identified in murine embryonic stem cells and is upregulated in various cancers. However, the expression and potential role of ERas in pancreatic cancer have not been investigated. In this study, we found that ERas mRNA and protein were upregulated in pancreatic cancer tissues and cells compared with controls. Knockdown of ERas in pancreatic cancer cells by siRNA significantly decreased cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis in vitro. Epithelial-mesenchymal transition (EMT) is closely related to tumor progression. We observed a significant decrease in N-cadherin expression in pancreatic cancer cells in response to ERas gene silencing by immunofluorescence assay and western blot. Furthermore, tumor growth and EMT were inhibited in xenografts derived from pancreatic cancer cells with ERas downregulation. We further investigated the regulatory mechanisms of ERas in pancreatic cancer and found that ERas may activate the Erk/Akt signaling pathway. Moreover, Erk inhibitor decreased pancreatic cancer cells proliferation and colony formation activities. Our data suggest that targeting ERas and its relevant signaling pathways might represent a novel therapeutic approach for the treatment of pancreatic cancer.


Assuntos
Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Sistema de Sinalização das MAP Quinases/genética , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/fisiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos Nus , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Proteína Oncogênica p21(ras)/metabolismo , Neoplasias Pancreáticas/terapia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/uso terapêutico , Transdução de Sinais/fisiologia , Regulação para Cima/genética
3.
Nucleic Acids Res ; 48(14): 7623-7639, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32644123

RESUMO

RNA therapeutics are a promising strategy to treat genetic diseases caused by the overexpression or aberrant splicing of a specific protein. The field has seen major strides in the clinical efficacy of this class of molecules, largely due to chemical modifications and delivery strategies that improve nuclease resistance and enhance cell penetration. However, a major obstacle in the development of RNA therapeutics continues to be the imprecise, difficult, and often problematic nature of most methods used to measure cell penetration. Here, we review these methods and clearly distinguish between those that measure total cellular uptake of RNA therapeutics, which includes both productive and non-productive uptake, and those that measure cytosolic/nuclear penetration, which represents only productive uptake. We critically analyze the benefits and drawbacks of each method. Finally, we use key examples to illustrate how, despite rigorous experimentation and proper controls, our understanding of the mechanism of gymnotic uptake of RNA therapeutics remains limited by the methods commonly used to analyze RNA delivery.


Assuntos
RNA/metabolismo , RNA/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Núcleo Celular/metabolismo , Citosol/metabolismo , Doenças Genéticas Inatas/tratamento farmacológico , Técnicas Genéticas , Humanos , MicroRNAs/uso terapêutico , Microscopia Eletrônica , Oligonucleotídeos Antissenso/uso terapêutico , RNA/química , RNA/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Espectrometria de Fluorescência
6.
Rev Neurol (Paris) ; 176(6): 507-515, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-88673

RESUMO

In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2months concerning treatments usually administered in hospitalization. NM patients treated with steroid/immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Doenças Neuromusculares/terapia , Pandemias , Pneumonia Viral/epidemiologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Aptidão Cardiorrespiratória , Infecções por Coronavirus/tratamento farmacológico , Tratamento de Emergência , França/epidemiologia , Doença de Depósito de Glicogênio Tipo II/terapia , Hospitalização , Humanos , Hidroxicloroquina/uso terapêutico , Doenças do Sistema Imunitário/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Modalidades de Fisioterapia , Pneumonia Viral/tratamento farmacológico , Prognóstico , RNA Interferente Pequeno/uso terapêutico , Esteroides/uso terapêutico , Suspensão de Tratamento , alfa-Glucosidases/uso terapêutico
7.
Rev Neurol (Paris) ; 176(6): 507-515, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32354651

RESUMO

In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2months concerning treatments usually administered in hospitalization. NM patients treated with steroid/immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Doenças Neuromusculares/terapia , Pandemias , Pneumonia Viral/epidemiologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Aptidão Cardiorrespiratória , Infecções por Coronavirus/tratamento farmacológico , Tratamento de Emergência , França/epidemiologia , Doença de Depósito de Glicogênio Tipo II/terapia , Hospitalização , Humanos , Hidroxicloroquina/uso terapêutico , Doenças do Sistema Imunitário/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Modalidades de Fisioterapia , Pneumonia Viral/tratamento farmacológico , Prognóstico , RNA Interferente Pequeno/uso terapêutico , Esteroides/uso terapêutico , Suspensão de Tratamento , alfa-Glucosidases/uso terapêutico
8.
Cochrane Database Syst Rev ; 4: CD012395, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32311072

RESUMO

BACKGROUND: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors. OBJECTIVES: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs). SEARCH METHODS: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites. SELECTION CRITERIA: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP. AUTHORS' CONCLUSIONS: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/mortalidade , Benzoxazóis/efeitos adversos , Benzoxazóis/uso terapêutico , Diflunisal/efeitos adversos , Diflunisal/uso terapêutico , Progressão da Doença , Humanos , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/uso terapêutico , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Qualidade de Vida , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
N Engl J Med ; 382(16): 1507-1519, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32187462

RESUMO

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Injeções Subcutâneas/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Fatores de Risco
12.
Cardiovasc Drugs Ther ; 34(3): 357-370, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32062791

RESUMO

PURPOSE: The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. METHODS: Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. RESULTS: Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. CONCLUSIONS: Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. CLINICAL TRIAL REGISTRATION: NCT02319005.


Assuntos
Neuropatias Amiloides Familiares/terapia , Cardiomiopatias/tratamento farmacológico , Pré-Albumina/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Adulto , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Canadá , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Causas de Morte , Progressão da Doença , Término Precoce de Ensaios Clínicos , Europa (Continente) , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Pré-Albumina/metabolismo , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Terapêutica com RNAi/efeitos adversos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
14.
Curr Atheroscler Rep ; 22(2): 10, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034521

RESUMO

PURPOSE OF REVIEW: Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS: RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Longo não Codificante/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Animais , Apolipoproteína C-III/antagonistas & inibidores , Aterosclerose/metabolismo , Humanos , Lipoproteína(a)/antagonistas & inibidores , Lipoproteína(a)/metabolismo , Fígado/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia
16.
Annu Rev Med ; 71: 203-219, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986086

RESUMO

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Insuficiência Cardíaca/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/terapia , Amiloidose/diagnóstico , Amiloidose/metabolismo , Amiloidose/terapia , Arritmias Cardíacas/terapia , Benzoatos/uso terapêutico , Benzoxazóis/uso terapêutico , Biópsia , Estimulação Cardíaca Artificial , Cardiomiopatias/epidemiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Diflunisal/uso terapêutico , Progressão da Doença , Diagnóstico Precoce , Intervenção Médica Precoce , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Fatores Imunológicos/uso terapêutico , Imagem por Ressonância Magnética , Oligonucleotídeos/uso terapêutico , Pré-Albumina/genética , Prognóstico , Inibidores de Proteassoma/uso terapêutico , Pirazóis/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Cintilografia
17.
Curr Opin Nephrol Hypertens ; 29(2): 180-189, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31895165

RESUMO

PURPOSE OF REVIEW: To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. RECENT FINDINGS: Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease. SUMMARY: Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.


Assuntos
Angiotensinogênio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Angiotensinogênio/genética , Animais , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos
18.
Exp Neurol ; 326: 113179, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31930990

RESUMO

Subarachnoid hemorrhage (SAH) is the most devastating form of stroke. Reducing neuronal apoptosis is an important countermeasure against early brain injury (EBI) after SAH. Recent evidence indicates that OX40-OX40L coupling is critical for cell survival and proliferation. Current study was performed to detect the role of recombinant OX40 (ReOX40) against neuronal apoptosis after SAH. The endovascular perforation model of SAH was performed on Sprague-Dawley (SD) rats. ReOX40 was injected intracerebroventricularly (i.c.v) 1 h after SAH induction and the following methods were employed: neurological function evaluation, immunofluorescence staining, fluoro-Jade C staining, and western blot. To study the underlying precise molecular mechanism, small interfering ribonucleic acid (siRNA) for OX40L and a specific inhibitor of PI3K, LY294002, were injected i.c.v. into SAH + ReOX40 rats before induction of SAH. When compared with sham rats, the expression of OX40 and OX40L was seen to decrease in the brain at 24 h after SAH induction. Administration of ReOX40 (5 µg/kg) increased expression of the OX40L, reduced the neuronal apoptosis, and improved short and long-term neurological function deficits. Furthermore, ReOx40 heightened activation of OX40L/PI3K/AKT axis, increased the downstream anti-apoptotic protein (Bcl2, Bcl-XL), and depressed the apoptotic protein (cleaved caspase 3, Bax). However, the protective effects of ReOX40 were abolished by the administration of OX40L siRNA and LY294002, respectively. These results demonstrate that ReOX40 attenuates neuronal apoptosis through OX40-OX40L/PI3K/AKT pathway in EBI after SAH.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores OX40/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/genética , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Injeções Intraventriculares , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Proteína Oncogênica v-akt/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores OX40/farmacologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Fatores de Necrose Tumoral
19.
Pharm Dev Technol ; 25(4): 408-415, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31847658

RESUMO

Introduction: Glioblastoma (GB) is the most common malignant brain tumor and is characterized by high invasiveness, poor prognosis, and limited therapeutic options. Silencing gene expression, through the use of small interfering RNA (siRNA), has been proposed as an alternative to conventional cancer therapy. Here, we evaluated the potential of CD73 as a new therapeutic target, since it is overexpressed in solid tumors and has emerged as a promising target to control GB progression.Methods: A cationic nanoemulsion (NE) as an intravenous siRNA-CD73 delivery system was developed and its effect on C6 glioma cell viability was determined.Results: The nanostructured system was effective in complexing oligonucleotides for delivery to target cells. In addition, we observed that the NE-siRNA-CD73 complex was effective in reducing CD73 protein levels and AMPase activity, which were related to decreased C6 glioma cell viability.Conclusions: These findings indicate the potential of siRNA-CD73-loaded cationic NE as a therapeutic alternative for glioma treatment.


Assuntos
5'-Nucleotidase/genética , Glioma/terapia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Cátions/química , Linhagem Celular Tumoral , Células Cultivadas , Portadores de Fármacos/química , Emulsões/química , Glioma/genética , RNA Interferente Pequeno/genética , Terapêutica com RNAi , Ratos
20.
Methods Mol Biol ; 2059: 167-189, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31435921

RESUMO

In current cancer therapy, the combined targeted delivery of treatments is an important method to enhance the therapeutic efficiency and reduce adverse side effects. Dendrimer-based nanoparticles have received considerable attention for multifunctional therapeutic delivery. In this chapter, we describe the methods for encapsulating the chemotherapeutic drug, cisplatin (CDDP), and human antigen R (HuR)-targeted siRNA into dendrimer nanoparticles for folate receptor-targeted delivery. We discuss the methodologies for physical and biological characterization of synthesized multifunctional (Den-PEI-CDDP-HuR-FA) nanoparticles in detail. Physical characterization includes size and charge determination, drug encapsulation and release kinetics, ligand conjugation, etc., and functional characterization involves testing of the nanoparticles for receptor-specific uptake and cytotoxicity on human lung cancer and normal cells. The protocol provided is geared to provide the readers an overview of developing multifunctional dendrimer-based nanoparticles. However, based on the individual's objective and the type of combinatorial drugs to deliver, the protocol may need modifications in achieving maximal efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Dendrímeros/química , Proteína Semelhante a ELAV 1/genética , Neoplasias Pulmonares/terapia , Nanopartículas/administração & dosagem , RNA Interferente Pequeno/genética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Terapia Combinada , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , RNA Interferente Pequeno/uso terapêutico , Fluxo de Trabalho
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