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1.
Rinsho Ketsueki ; 60(9): 1275-1282, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597853

RESUMO

Hemophilia is a congenital bleeding disorder that occurs due to quantitative and functional abnormalities of FVIII or FIX. It has a long history, dating as far back as the Babylonian era, with many high profile reports, including the British royal family and the last prince of the Romanov dynasty. The treatment used to be blood transfusion, consisting of plasma derived products from the 1970s onwards and recombinant products introduced later in the 1990s. In the 2000s, due to various modifications of factor protein, extended half-life (EHL) products have appeared and replaced conventional products. In EHL research, new products are also being developed that further the extension of the half-life and are more convenient. In 2018, an antibody-based medicine arrived, exhibiting a mechanism different from factor replacement therapy. Some other therapeutic agents used to suppress bleeding, called nonfactor agents, are currently under development. Recently, gene therapy has finally come into the clinical trial space in Japan and can be expected to be a treatment which aims at "cure," as it can be used with no exposure to bleedings for several years with one injection. This article outlines the future of hemophilia treatment.


Assuntos
Hemofilia A/terapia , Hemofilia B/terapia , Fator IX , Fator VIII , Terapia Genética/tendências , Hemostáticos/uso terapêutico , Humanos , Japão
2.
Rinsho Ketsueki ; 60(9): 1358-1365, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597864

RESUMO

The former definition of gene therapy was the infusion of genes or cells transduced with genes into humans for the treatment or prevention of a disease, i.e., gene therapy adds a functional gene into the patients' genome, whereas the mutated gene remains as it is. Because most of the immune immunodeficiency disorders (PID) are caused by single gene mutations, this therapeutic option may provide a clinical effect. However, the treatment has a severe problem of leukemogenesis caused by insertional mutagenesis; therefore, it is not applicable for diseases caused by the gain-of-function of mutated genes. To address this, gene therapy using gene correction techniques will come to the forefront of the mainstream research. Herein, I have focused on the present outline of gene therapy by gene addition and described the future prospects of gene therapy by gene correction for PID.


Assuntos
Terapia Genética , Síndromes de Imunodeficiência/terapia , Humanos
3.
Rev Prat ; 69(6): 659-665, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-31626429

RESUMO

Primary immune deficiencies (PIDs) include rare and heterogeneous syndromes due to genetic abnormalities involving the immune system. In the registry of the French National Reference Center for Primary Immune Deficiencies (CEREDIH), the median age of clinical onset is 2 years, but 25% of patients develop the first symptoms after 15 years. A diagnosis of PID should be considered in the presence of an unusual association of infections, autoimmune pathologies, granulomatous disease, polyclonal lymphoproliferation or atypical lymphoma. PID management currently benefits from new antibiotic prophylaxis, the improvement of allogeneic hematopoietic stem cell transplantation procedure and the development of gene therapy. In addition, the understanding of the pathophysi ological mechanisms led to new treatments targeting the pathways implicated by the genetic defects. In this review, we briefly recall the classification of PID. We illustrate the problem of PID in adults with clinical cases and then summarize the main principles of management in adults PID patients.


Assuntos
Síndromes de Imunodeficiência , Adulto , Criança , Pré-Escolar , Terapia Genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Sistema de Registros
4.
Medicina (B Aires) ; 79 Suppl 3: 77-81, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603849

RESUMO

Duchenne muscular dystrophy is a genetically determined disease, linked to the X chromosome, c haracterized clinically by producing progressive muscle weakness, with an incidence of 1 per 3500-6000 males born. It is caused by the mutation of the DMD gene, which encodes dystrophin, a sub-sarcolemmal protein essential for structural muscle stability. The genetic defects in the DMD gene are divided into: deletions (65%) duplications (5.10%) and point mutations (10-15%). At present there is no curative treatment, the only drug that has been shown to modify the natural history of the disease (independently of the genetic mutation) are corticosteroids, currently indicated in early stages of the disease. In relation to clinical trials, in the last ten years, has experienced great advances in the field of therapeutic options, divided into two major therapeutic targets: 1) the area of gene therapies and 2) trying to reverse or block the pathophysiological processes of the disease, such as inflammation, fibrosis, muscle regeneration, etc. It is likely that an effective treatment for Duchenne muscular dystrophy requires combinations of therapies that address both the primary defect and its secondary pathophysiological consequences.


Assuntos
Terapia Genética/métodos , Distrofia Muscular de Duchenne/terapia , Animais , Sistemas CRISPR-Cas , Distrofina/genética , Genótipo , Humanos , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/genética , Fenótipo
5.
Cad. Ibero Am. Direito Sanit. (Impr.) ; 8(3): 48-59, jul.-set. 2019.
Artigo em Português | LILACS | ID: biblio-1022852

RESUMO

Objetivo: discutir o processo regulatório de medicamentos para doenças raras no Brasil, com base no caso Zolgensma®, e avaliar criticamente as evidências disponíveis até o momento sobre a eficácia e a segurança do Zolgensma® no tratamento da atrofia muscular espinhal (AME). Metodologia: estudo descritivo realizado no Núcleo de Avaliação de Tecnologias em Saúde do Hospital Sírio-Libanês (NATS-HSL) em junho de 2019. Resultados: em abril de 2019, o uso do Zolgensma® para AME foi regulamentado nos Estados Unidos com base em dois estudos clínicos abertos (sem mascaramento), sem grupo comparador paralelo (e, portanto, não randomizados). Essas limitações metodológicas aumentam a incerteza nos resultados encontrados. A Agência Nacional de Vigilância Sanitária (Anvisa) aprovou estratégias para regulamentar o processo e os prazos de análise das submissões de registro de novos medicamentos para doenças raras, caso do Zolgensma®. Conclusão: faz-se necessário ampliar o debate em torno do processo de regulamentação e de incorporação de medicamentos órfãos para doenças raras no Brasil. O debate deve incluir as evidências relacionadas aos efeitos ­ benefícios e riscos ­ desses medicamentos, e maior clareza nos critérios para concessão de registro e recomendação de incorporação em sistemas de saúde. (AU).


Objective: to discuss the regulatory process of drugs for rare diseases in Brazil, based on the Zolgensma® case, and to critically evaluate the evidence so far available on the efficacy and safety of Zolgensma® for treating spinal muscular atrophy (SMA). Methods: descriptive study conducted at the Health Technology Assessment Center of the Sírio Libanês Hospital (NATS-HSL) in June 2019. Results: in April 2019, the use of Zolgensma® for SMA was regulated in the United States based on two open-lable (unmasked), non-comparative (and therefore non-randomized) studies. These methodological limitations increase the uncertainty related to study results. The National Agency of Sanitary Surveillance (Anvisa) has approved strategies to regulate the process and specific deadlines for completing the appraisal process of new medicines for rare diseases, such as Zolgensma®. Conclusion: it is necessary to broaden the debate about the process of regulation and incorporation of orphan drugs for rare diseases in Brazil. This debate should include evidence related to the effects (benefits and risks) of these drugs, and greater transparency of the criteria indispensable for granting registration and recommendation of incorporation into health systems. (AU).


Objetivo: analizar el proceso de fármacos reguladores para enfermedades raras en Brasil, con base en el caso Zolgensma, y para evaluar críticamente la evidencia disponible hasta el momento sobre la eficacia y seguridad de Zolgensma® nel tratamiento de atrofia muscular espinal (AME). Métodos: estudio descriptivo realizado en el Centro de Evaluación de Tecnología de Salud del Hospital Sírio-Libanês (NATS-HSL) en junio de 2019. Resultados: en abril de 2019, el uso de Zolgensma® para la AME se reguló en los Estados Unidos basado en dos estudios abiertos (no enmascarados), no comparativos (y por lo tanto no aleatorios). Estas limitaciones metodológicas aumentan la incertidumbre en los resultados encontrados. La Agencia Nacional de Vigilancia Sanitaria en Brasil (Anvisa) ha aprobado estrategias para regular el proceso y los plazos de análisis de las solicitudes de registro de nuevos fármacos para enfermedades raras, el caso de Zolgensma. Conclusión: es necesario ampliar el debate sobre el proceso de regulación e incorporación de medicamentos huérfanos para enfermedades raras en Brasil. Este debate debe incluir evidencia relacionada con los efectos (beneficios y riesgos) de estos medicamentos y una mayor transparencia en los criterios para otorgar el registro y la recomendación de incorporación a los sistemas de salud. (AU).


Assuntos
Atrofia Muscular Espinal , Terapia Genética , Doenças Raras , Registro de Produtos , Medicamentos do Componente Especializado da Assistência Farmacêutica
6.
Cancer Radiother ; 23(5): 449-465, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400956

RESUMO

Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Genética/métodos , Lesões por Radiação/prevenção & controle , Proteção Radiológica/métodos , Amifostina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Edição de Genes , Vetores Genéticos/uso terapêutico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Camundongos , Oxirredutases/genética , Oxirredutases/uso terapêutico , Lesões por Radiação/etiologia , Lesões por Radiação/terapia , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/terapia , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo
8.
Adv Exp Med Biol ; 1158: 217-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452143

RESUMO

Mitochondria maintain and express their own genome, referred to as mtDNA, which is required for proper mitochondrial function. While mutations in mtDNA can cause a heterogeneous array of disease phenotypes, there is currently no cure for this collection of diseases. Here, we will cover characteristics of the mitochondrial genome important for understanding the pathology associated with mtDNA mutations, and review recent approaches that are being developed to treat and prevent mtDNA disease. First, we will discuss mitochondrial replacement therapy (MRT), where mitochondria from a healthy donor replace maternal mitochondria harbouring mutant mtDNA. In addition to ethical concerns surrounding this procedure, MRT is only applicable in cases where the mother is known or suspected to carry mtDNA mutations. Thus, there remains a need for other strategies to treat patients with mtDNA disease. To this end, we will also discuss several alternative means to reduce the amount of mutant mtDNA present in cells. Such methods, referred to as heteroplasmy shifting, have proven successful in animal models. In particular, we will focus on the approach of targeting engineered endonucleases to specifically cleave mutant mtDNA. Together, these approaches offer hope to prevent the transmission of mtDNA disease and potentially reduce the impact of mtDNA mutations.


Assuntos
Terapia Genética , Doenças Mitocondriais , Animais , DNA Mitocondrial , Modelos Animais de Doenças , Terapia Genética/tendências , Genoma Mitocondrial , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/terapia , Mutação
9.
Adv Exp Med Biol ; 1158: 257-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452145

RESUMO

Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of heteroplasmy, with coexistence of pathogenic and wild type mtDNA. The load of heteroplasmy, defined as the relative amount of pathogenic mtDNA to wild type mtDNA, corresponds to timing and symptom severity. Thus, changing the heteroplasmy load may lead to a shift in disease onset and symptom severity. Here we review techniques aimed at preventing inheritance of pathogenic mtDNA via mitochondrial replacement therapy (MRT) and strategies geared toward shifting of heteroplasmy in individuals with active mitochondrial disease. MRT strategies seek to create embryos with the nuclear genetic makeup of the intended parents and wild type mtDNA from a donor in order to avoid known maternal pathogenic variants. Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.


Assuntos
Terapia Genética , Doenças Mitocondriais , Animais , Núcleo Celular , DNA Mitocondrial/genética , Terapia Genética/tendências , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/terapia
10.
Br J Anaesth ; 123(4): 439-449, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383364

RESUMO

BACKGROUND: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms. METHODS: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. RESULTS: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. CONCLUSIONS: Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.


Assuntos
Terapia Genética/métodos , Lentivirus/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Crescimento Neural/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Arritmias Cardíacas/prevenção & controle , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Injeções Espinhais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/prevenção & controle , Fator de Crescimento Neural/biossíntese , Células PC12 , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
12.
J Nanobiotechnology ; 17(1): 86, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387581

RESUMO

BACKGROUND: Controllable and multiple DNA release is critical in modern gene-based therapies. Current approaches require complex assistant molecules for combined release. To overcome the restrictions on the materials and environment, a novel and versatile DNA release method using a nano-electromechanical (NEMS) hypersonic resonator of gigahertz (GHz) frequency is developed. RESULTS: The micro-vortexes excited by ultra-high frequency acoustic wave can generate tunable shear stress at solid-liquid interface, thereby disrupting molecular interactions in immobilized multilayered polyelectrolyte thin films and releasing embedded DNA strands in a controlled fashion. Both finite element model analysis and experiment results verify the feasibility of this method. The release rate and released amount are confirmed to be well tuned. Owing to the different forces generated at different depth of the films, release of two types of DNA molecules with different velocities is achieved, which further explores its application in combined gene therapy. CONCLUSIONS: Our research confirmed that this novel platform based on a nano-electromechanical hypersonic resonator works well for controllable single and multi-DNA release. In addition, the unique features of this resonator such as miniaturization and batch manufacturing open its possibility to be developed into a high-throughput, implantable and site targeting DNA release and delivery system.


Assuntos
DNA/química , Nanoestruturas/química , Polieletrólitos/química , Acústica/instrumentação , Fenômenos Biofísicos , Desenho de Equipamento , Análise de Elementos Finitos , Técnicas de Transferência de Genes , Terapia Genética/métodos , Membranas Artificiais , Propriedades de Superfície
13.
Gene ; 719: 144071, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31454539

RESUMO

RNA interference (RNAi) has extensive potential to revolutionize every aspect of clinical application in biomedical research. One of the promising tools is the Small interfering RNA (siRNA) molecules within a cellular component. Principally, siRNA mediated innovative advances are increasing rapidly in support of cancer diagnosis and therapeutic purposes. Conversely, it has some delivery challenges to the site of action within the cells of a target organ, due to the progress of nucleic acids engineering and advance material science research contributing to the exceptional organ-specific targeted therapy. This siRNA based therapeutic technique definitely favors a unique and effective prospect to cancer patients. Herein, the significant drive also takes to review and summarize the major organ specific targets of diverse siRNAs based gene silencing mechanism. This machinery promisingly served as the inhibitor components for cancer development in the human model. Furthermore, the focus is also given to current applications on siRNA based quantifiable therapy leading to the silencing of cancer related gene expression in a sequence dependent and selective manner for cancer treatment. That might be a potent tool against the traditional chemotherapy techniques. Therefore, the siRNA mediated cancer gene therapy definitely require sharp attention like future weapons in opposition to cancer by the method of non-invasive siRNA delivery and effective gene silencing approaches.


Assuntos
Terapia Genética/métodos , Neoplasias/terapia , RNA Interferente Pequeno/uso terapêutico , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Ligação Proteica , RNA Interferente Pequeno/metabolismo
14.
Cell Mol Life Sci ; 76(21): 4203-4219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300868

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismo
15.
J Nanobiotechnology ; 17(1): 80, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277667

RESUMO

BACKGROUND: The gastric cancer is the second most malignant tumor in the world. HER-2 is one of the key targets for the gastric cancer therapy. Anti-HER-2 antibodies like trastuzumab, exhibits the satisfactory therapeutic effect in clinical. However, the drug resistance problem limits its application. METHOD: In this study, we develop a gold nanoshell (Gold Nanoshell) drug carrier for delivery and selective photo-thermal release of genes which target HER-2 and immunologic adjuvant CPG sequence in gastric tumor cells. The drug delivery system generated a multidimensional treatment strategy which includes gene-, immune- and photothermal-therapy. RESULTS: The whole gold nanoshell drug delivery system exhibits the well gene transduction ability and combined treatment effect. Both in vitro and in vivo results demonstrate the multiple therapeutic effects of the drug delivery system is better than the monotherapy. CONCLUSIONS: This study indicates the multiple combined therapy based on the gold nanoshell system would be a promising translational treatment for gastric cancer.


Assuntos
Ouro/química , Nanoconchas/química , Neoplasias Gástricas/terapia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Terapia Genética , Humanos , Hipertermia Induzida , Imunoterapia , Camundongos Nus , Terapia de Alvo Molecular , Fototerapia , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia
16.
Nat Commun ; 10(1): 2993, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278269

RESUMO

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.


Assuntos
Terapia Genética/métodos , Cirrose Hepática Experimental/terapia , Neoplasias Hepáticas/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Relaxina/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Linhagem Celular Tumoral/transplante , Progressão da Doença , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Plasmídeos/genética , Receptores Acoplados a Proteínas-G/metabolismo , Relaxina/metabolismo , Resultado do Tratamento , Microambiente Tumoral/genética , Regulação para Cima
19.
Nervenarzt ; 90(8): 809-816, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-31286145

RESUMO

BACKGROUND: For a long time the treatment of neuromuscular diseases was considered to be purely symptomatic. Due to new technologies in recent years novel causal forms of treatment could be developed. Gene therapies for spinal muscular atrophy, Duchenne muscular dystrophy, limb-girdle muscular dystrophy, myotubular myopathy and hereditary motor and sensory neuropathy type 1A are currently being evaluated in clinical trials. Initial preliminary results are promising and the first preparation onasemnogene abeparvovec-xioi (Zolgensma®) for the treatment of spinal muscular atrophy has recently been approved by the U.S. Food and Drug Administration (FDA). OBJECTIVE: This review describes the principles of gene therapy, summarizes the interim results published so far and provides an overview of currently active or soon to be initiated gene therapy trials. CONCLUSION: Gene therapies have the potential to significantly influence the course of neuromuscular diseases. First positive intermediate results have been published and the first treatment has recently been approved in the USA. Long-term data on sustained effects and toxicity of gene therapies are not yet available. These novel treatment options will present new challenges for the healthcare systems concerning diagnosis, treatment and reimbursement.


Assuntos
Terapia Genética , Doenças Neuromusculares , Terapia Genética/tendências , Humanos , Doenças Neuromusculares/terapia
20.
Pharm Res ; 36(9): 133, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289919

RESUMO

PURPOSE: KRAS is the most frequently mutated gene in human cancers. Despite its direct involvement in malignancy and intensive effort, direct inhibition of KRAS via pharmacological inhibitors has been challenging. RNAi induced knockdown using siRNAs against mutant KRAS alleles offers a promising tool for selective therapeutic silencing in KRAS-mutant lung cancers. However, the major bottleneck for clinical translation is the lack of efficient biocompatible siRNA carrier systems. METHODS: Bovine serum albumin (BSA) nanoparticles were prepared by desolvation method to deliver siRNA targeting the KRAS G12S mutation. The BSA nanoparticles were characterized with respect to their size, zeta potential, encapsulation efficiency and nucleic acid release. Nanoparticle uptake, cellular distribution of nucleic acids, cytotoxicity and gene knock down to interfere with cancer hallmarks, uncontrolled proliferation and migration, were evaluated in KRAS G12S mutant A459 cells, a lung adenocarcinoma cell line. RESULTS: BSA nanoparticles loaded with siRNA resulted in nanoparticles smaller than 200 nm in diameter and negative zeta potentials, displaying optimal characteristics for in vivo application. Encapsulating and protecting the siRNA payload well, the nanoparticles enabled transport to A549 cells in vitro, could evade endosomal entrapment and mediated significant sequence-specific KRAS knockdown, resulting in reduced cell growth of siRNA transfected lung cancer cells. CONCLUSIONS: BSA nanoparticles loaded with mutant specific siRNA are a promising therapeutic approach for KRAS-mutant cancers.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Interferente Pequeno/farmacologia , Soroalbumina Bovina/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Bovinos , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Terapia Genética , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Transfecção
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