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2.
Biol Pharm Bull ; 42(10): 1679-1688, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582656

RESUMO

Targeted drug delivery system (DDS) is required for RNA interference (RNAi) therapy to increase the therapeutic effect and to reduce the adverse effect. Especially in transthyretin (TTR)-related amyloidosis, hepatocyte specific delivery is desired because TTR mainly expresses in hepatocyte. Herein, we report on a hepatocyte-specific small interfering RNA (siRNA) delivery system using polyethylene glycol (PEG)-modified lactosylated dendrimer (generation 3; G3) conjugates with α-cyclodextrin (PEG-LαCs (G3)) for TTR-related amyloidosis therapy, and investigated the in vitro and in vivo gene silencing effect of PEG-LαCs (G3)/siRNA polyplexes. PEG-LαC (G3, average degree of substitution of PEG (DSP) 2)/TTR siRNA (siTTR) polyplex exhibited the asialoglycoprotein receptor (ASGPR)-mediated cellular uptake, high endosomal escaping ability and localization of the siRNA in cytoplasm, resulting in significant TTR silencing in HepG2 cells. In vivo studies showed that PEG-LαC (G3, DSP2)/siTTR polyplex led to a significant TTR silencing effect in liver after systemic administration to mice. Furthermore, safety evaluation revealed that PEG-LαC (G3, DSP2)/siTTR polyplex had no significant toxicity both in vitro and in vivo. These findings suggest the utility of PEG-LαC (G3, DSP2) as a promising hepatocyte-specific siRNA delivery system both in vitro and in vivo, and as a therapeutic approach for TTR-related amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Ciclodextrinas/administração & dosagem , Dendrímeros/administração & dosagem , Hepatócitos/metabolismo , Polietilenoglicóis/administração & dosagem , Pré-Albumina/genética , RNA Interferente Pequeno/administração & dosagem , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Animais , Dendrímeros/farmacocinética , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/farmacocinética , Pré-Albumina/metabolismo , RNA Interferente Pequeno/farmacocinética
9.
Expert Rev Clin Pharmacol ; 12(8): 701-711, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268366

RESUMO

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Polineuropatias/tratamento farmacológico , Adulto , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Animais , Humanos , Mutação , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Polineuropatias/etiologia , Pré-Albumina/genética , Qualidade de Vida
10.
Amyloid ; 26(3): 103-111, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339362

RESUMO

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Gerenciamento Clínico , Glaucoma/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Adulto , Idade de Início , Idoso , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Consenso , Progressão da Doença , Feminino , Glaucoma/tratamento farmacológico , Glaucoma/genética , Glaucoma/fisiopatologia , Testes de Função Cardíaca , Neuropatias Hereditárias Sensoriais e Autônomas/tratamento farmacológico , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Mutação , Fármacos Neuroprotetores/uso terapêutico , Pré-Albumina/deficiência , Pré-Albumina/genética
15.
Nat Rev Neurol ; 15(7): 387-404, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209302

RESUMO

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis with polyneuropathy (also known as familial amyloid polyneuropathy) is a condition with adult onset caused by mutation of transthyretin (TTR) and characterized by extracellular deposition of amyloid and destruction of the somatic and autonomic PNS, leading to loss of autonomy and death. This disease represents a model of the scientific and medical progress of the past 30 years. ATTRv amyloidosis is a worldwide disease with broad genetic and phenotypic heterogeneity that presents a diagnostic challenge for neurologists. The pathophysiology of the neuropathy is increasingly understood and includes instability and proteolysis of mutant TTR leading to deposition of amyloid with variable lengths of fibrils, microangiopathy and involvement of Schwann cells. Wild-type TTR is amyloidogenic in older individuals. The main symptoms are neuropathic, but the disease is systemic; neurologists should be aware of cardiac, eye and kidney involvement that justify a multidisciplinary approach to management. Infiltrative cardiomyopathy is usually latent but present in half of patients. Disease-modifying therapeutics that have been developed include liver transplantation and TTR stabilizers, both of which can slow progression of the disease and increase survival in the early stages. Most recently, gene-silencing drugs have been used to control disease in the more advanced stages and produce some degree of improvement.


Assuntos
Neuropatias Amiloides Familiares/genética , Pré-Albumina/genética , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/patologia , Progressão da Doença , Humanos , Mutação , Células de Schwann/patologia
16.
Drugs Today (Barc) ; 55(5): 315-327, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131842

RESUMO

Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both mutant and wild-type amyloid transthyretin (ATTR) protein production becomes suppressed. This drug was developed by Alnylam Pharmaceuticals to treat a rare disease called hereditary ATTR (hATTR) amyloidosis. This disease develops as a result of the deposition of toxic aggregates of misfolded TTR protein, and is progressive causing the affected individual to be bed bound and to eventually die if left untreated. However, variable expressivity and incomplete penetrance cause carriers of TTR gene variants to be asymptomatic for a prolonged time. The heterogeneity of symptoms makes correct diagnosis of the disease difficult, therefore management of symptoms and proper treatment are delayed as a result. However, certain TTR variants are found in endemic or cluster regions, which facilitates their detection. In this review paper, different aspects of the drug are discussed in detail, including its preclinical and clinical studies, as well as its pharmacokinetic properties along with drug interactions leading to its approval by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Humanos , Nanopartículas , RNA Mensageiro , Estados Unidos
17.
Amyloid ; 26(2): 74-84, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31119947

RESUMO

Objective: To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. Methods: A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200 mg dose of tolcapone; phase B: three 100 mg doses taken at 4 h intervals. The primary efficacy variable was TTR stabilization. Results: Seventeen subjects were included (wild type, n = 6; mutation TTR Val30Met, n = 11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2 h after dosing, which decreased to 22.9% at 8 h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2 h after the first 100 mg dose. This difference was maintained after 10 h and decreased after 24 h. No serious adverse events were observed. Conclusions: The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. EudraCT trial number: 2014-001586-27 ClinicalTrials.gov Identifier: NCT02191826.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Pré-Albumina/metabolismo , Estudo de Prova de Conceito , Agregação Patológica de Proteínas/prevenção & controle , Tolcapona/uso terapêutico , Adulto , Idoso , Neuropatias Amiloides Familiares/metabolismo , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Pré-Albumina/genética , Tolcapona/farmacologia
18.
Drug Des Devel Ther ; 13: 1515-1525, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118583

RESUMO

Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Animais , Humanos
19.
Drugs ; 79(8): 863-874, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31098895

RESUMO

Transthyretin amyloidosis with polyneuropathy (ATTR-PN), a rare and progressive hereditary disorder, results from mutations in the gene coding for the transthyretin (TTR) protein that destabilize the protein's tetrameric structure. In over 40 countries worldwide, tafamidis (Vyndaqel®) is approved for the treatment of TTR amyloidosis in adults with stage 1 symptomatic polyneuropathy, to delay peripheral neurological impairment. Tafamidis is administered orally once daily, as a soft capsule. Evidence from clinical studies, including an 18-month placebo-controlled trial and subsequent long-term, open-label extension studies (providing data from ≤ 6 years of treatment), indicate that tafamidis slowed deterioration of neurological function and maintained health-related quality of life in patients with early-stage ATTR-PN and the Val30Met mutation. TTR tetramers were stabilized in nearly all patients, and nutritional status was generally maintained or improved. Similar benefit was seen with tafamidis over 12 months in a noncomparative trial in patients with non-Val30Met ATTR-PN, although disease progression in this population (which was older and had had ATTR-PN for longer than Val30Met patients) became more notable with continued therapy in an extension study. Data for up to 10 years from large registry and referral centre studies support the long-term effectiveness and safety of tafamidis in delaying disease progression and conferring survival benefits in patients with stage 1 ATTR-PN. Tafamidis was generally well tolerated, with no new safety signals detected during the long-term trial or real-world experience. Thus, based on up to 10 years' experience, tafamidis continues to be a valuable option in the treatment of early-stage ATTR-PN.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/uso terapêutico , Polineuropatias/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Benzoxazóis/administração & dosagem , Benzoxazóis/farmacologia , Ensaios Clínicos como Assunto , Progressão da Doença , Aprovação de Drogas , Humanos , Mutação , Polineuropatias/genética , Pré-Albumina/genética , Pré-Albumina/metabolismo , Qualidade de Vida
20.
Amyloid ; 26(2): 55-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30907141

RESUMO

There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Pré-Albumina , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto , Neuropatias Amiloides/tratamento farmacológico , Neuropatias Amiloides/metabolismo , Neuropatias Amiloides/terapia , Neuropatias Amiloides Familiares/terapia , Benzoxazóis/uso terapêutico , Diflunisal/uso terapêutico , Feminino , Humanos , Masculino , Oligonucleotídeos/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Resultado do Tratamento
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