Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.383
Filtrar
1.
Urol Clin North Am ; 47(1): 93-101, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757304

RESUMO

Non-muscle-invasive bladder cancer is a challenging disease to treat, with few effective salvage intravesical options available for patients who develop bacillus Calmette-Guerin-unresponsive disease. Although radical cystectomy with pelvic lymphadenectomy remains the gold standard treatment for these patients, there remains an unmet need for other options for those who are unable or unwilling to undergo surgery. To this end, intravesical gene therapy is emerging as a potential alternative with promising early data and ongoing efforts to better understand the mechanisms of action to optimize therapy.


Assuntos
Terapia Genética/métodos , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Humanos
2.
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
3.
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
5.
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
6.
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
7.
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
8.
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
9.
Gene ; 714: 143968, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31323308

RESUMO

Sulfur mustard (SM) is a destructive and harmful chemical agent for the eyes, skin and lungs that causes short-term and long-term lesions and was widely used in Iraq war against Iran (1980-1988). SM causes DNA damages, oxidative stress, and Inflammation. Considering the similarities between SM and COPD (Chronic Obstructive Pulmonary Disease) pathogens and limited available treatments, a novel therapeutic approach is not developed. Gene therapy is a novel therapeutic approach that uses genetic engineering science in treatment of most diseases including chronic obstructive pulmonary disease. In this review, attempts to presenting a comprehensive study of mustard lung and introducing the genes therapy involved in chronic obstructive pulmonary disease and emphasizing the pathways and genes involved in the pathology and pathogenesis of sulfur Mustard. It seems that, given the high potential of gene therapy and the fact that this experimental technique is a candidate for the treatment of pulmonary diseases, further study of genes, vectors and gene transfer systems can draw a very positive perspective of gene therapy in near future.


Assuntos
Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Gás de Mostarda/efeitos adversos , Transdução de Sinais/genética , Animais , Terapia Genética/métodos , Humanos , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/genética
11.
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
12.
Nature ; 572(7767): 125-130, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341277

RESUMO

Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice. MDC1A is caused by mutations in LAMA2 that lead to nonfunctional laminin-α2, which compromises the stability of muscle fibres and the myelination of peripheral nerves. Transgenic overexpression of Lama1, which encodes a structurally similar protein called laminin-α1, ameliorates muscle wasting and paralysis in mouse models of MDC1A, demonstrating its importance as a compensatory modifier of the disease1. However, postnatal upregulation of Lama1 is hampered by its large size, which exceeds the packaging capacity of vehicles that are clinically relevant for gene therapy. We modulate expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis. However, for many disorders it is important to investigate the therapeutic window and reversibility of symptoms. In muscular dystrophies, it has been hypothesized that fibrotic changes in skeletal muscle are irreversible. However, we show that dystrophic features and disease progression were improved and reversed when the treatment was initiated in symptomatic dy2j/dy2j mice with apparent hindlimb paralysis and muscle fibrosis. Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR-dCas9-mediated upregulation of Lama1, which may enable mutation-independent treatment for all patients with MDC1A. This approach has a broad applicability to a variety of disease-modifying genes and could serve as a therapeutic strategy for many inherited and acquired diseases.


Assuntos
Genes Modificadores/genética , Terapia Genética/métodos , Laminina/genética , Laminina/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/terapia , Regulação para Cima , Animais , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Progressão da Doença , Feminino , Fibrose/metabolismo , Fibrose/patologia , Edição de Genes , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação
13.
Biotechnol Lett ; 41(8-9): 889-898, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31256273

RESUMO

OBJECTIVE: Several studies have investigated the role of gene therapy in the healing process. The aim of this review is to explain the gene delivery systems in wound area. RESULTS: Ninety-two studies were included and comprehensively overviewed. We described the importance of viral vectors such as adenoviruses, adeno-associated viruses, and retroviruses, and conventional non-viral vectors such as naked DNA injections, liposomes, gene gun, electroporation, and nanoparticles in achieving high-level expression of genes. Application of viral transfection, liposomal vectors, and electroporation were the main gene delivery systems. Genes encoding for growth factors or cytokines have been shown to result in a better wound closure in comparison to application of the synthetic growth factors. In addition, a combination of stem cell and gene therapy has been found an effective approach in regeneration of cutaneous wounds. CONCLUSIONS: This article gives an overview of the methods and investigations applied on gene therapy in wound healing. However, clinical investigations need to be undertaken to gain a better understanding of gene delivery technologies and their roles in stimulating wound repair.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Ferimentos e Lesões/terapia , Humanos
15.
J Stroke Cerebrovasc Dis ; 28(9): 2555-2562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31248739

RESUMO

OBJECTIVE: The present study aimed to investigate the effects of Mesenchymal stem cells/glial cell line derived neurotrophic factor (MSCs/GDNF) transplantation on nerve reconstruction in rats with intracerebral hemorrhage. METHODS: GDNF transduction to MSCs was using adenovirus vector pAdEasy-1-pAdTrack-CMV prepared. Intracerebral hemorrhage (ICH) was induced by injection of collagenase and heparin into the caudate putamen. At the third day after a collagenase-induced ICH, adult male SD rats were randomly divided into saline group, MSCs group and MSCs/GDNF group. Immunofluorescence and RT-PCR were performed to detect the differentiation of MSCs or MSCs with an adenovirus vector encoding GDNF gene in vivo and in vitro. RESULT: After 6 hours of induction, both MSCs and MSCs/GDNF expressed neuro or glial specific markers and synaptic-associated proteins (SYN, GAP-43, PSD-95); additionally, they secreted bioactive compounds (BDNF, NGF-ß). MSCs/GDNF transplantation, compared to MSCs and saline solution injection, significantly improved neurological functions after ICH. The grafted MSCs or MSCs/GDNF survived in the striatum after 2 weeks of transplantation and expressed the neural cell-specific biomarkers NSE, MAP2, and GFAP. CONCLUSION: These findings demonstrate that MSCs/GDNF transplantation contributes to improved neurological function in experimental ICH rats. The mechanisms are possibly due to neuronal replacement and enhanced neurotrophic factor secretion.


Assuntos
Encéfalo/fisiopatologia , Hemorragia Cerebral/cirurgia , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Regeneração Nervosa , Células-Tronco Neurais/transplante , Transfecção , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Masculino , Células-Tronco Neurais/metabolismo , Neurogênese , Fenótipo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Tempo
16.
Rom J Ophthalmol ; 63(1): 15-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198893

RESUMO

Objective. Corneal neovascularization is a sight-threatening condition affecting more than 1.4 million people per year. Left untreated, it can lead to tissue scarring, oedema, lipid deposition, and persistent inflammation that may significantly affect visual prognosis and quality of life. The aim was to review the recent evidence relating to the pathophysiology, investigations and management of corneal neovascularization. Methods. Literature review of prospective and retrospective studies, clinical trials and animal models relating to the pathophysiology, investigation and management of corneal neovascularization. Results. Corneal neovascularization is characterized by the invasion of new blood vessels into the cornea caused by an imbalance between angiogenic and antiangiogenic factors that preserve corneal transparency as a result of various ocular insults and hypoxic injuries. Risk factors that have been implicated in the pathogenesis of the disease include contact lens wear, ocular surface disease, trauma, previous surgery and herpes. The results highlighted the current and future management modalities of corneal neovascularization, which includes corneal transplantation, laser - phototherapy, injections and topical treatment. Conclusion. The future of corneal neovascularization is promising and this paper discusses the upcoming revolution in local gene therapy. Abbreviations. HSK = herpes stromal keratitis, VEGF = vascular endothelial growth factor, VEGFR-1 = VEGF Receptor-1, FGF = Fibroblast growth factor, PDGF = Platelet-derived growth factor, IL-6 = interleukin-6, IL-7 = interleukin-7, IL-8 = interleukin-8, IRS-1 = insulin receptor substrate-1.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Córnea/irrigação sanguínea , Neovascularização da Córnea , Gerenciamento Clínico , Terapia Genética/métodos , Ceratoplastia Penetrante/métodos , Acuidade Visual , Animais , Córnea/patologia , Neovascularização da Córnea/diagnóstico , Neovascularização da Córnea/fisiopatologia , Neovascularização da Córnea/terapia , Humanos
17.
Value Health ; 22(6): 621-626, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31198178

RESUMO

OBJECTIVES: To estimate, at the indication level, durable gene and cellular therapy new product launches in the United States through 2030, and the number of treated patients. METHODS: A statistical analysis of clinical trials pipeline data and disease incidence and prevalence was conducted to estimate the impact of new cell and gene therapies. We used Citeline's® Pharmaprojects® database to estimate the rates and timing of new product launches, on the basis of the phase of development, duration in phase, and probability of progression. Disease incidence and prevalence data were combined with estimates of market adoption to project the size of reimbursed patient populations. RESULTS: We project that about 350 000 patients will have been treated with 30 to 60 products by 2030. About half the launches are expected to be in B-cell (CD-19) lymphomas and leukemias. CONCLUSIONS: Cell and gene therapies promise durable clinical benefit from a single treatment course. High upfront reimbursement for these products means that the total costs could exceed what the healthcare system can manage. This creates a need for precision financing solutions and new reimbursement models that can ensure appropriate patient access to needed treatments, increase affordability for payers, and sustain private investment in innovation.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/economia , Terapia Genética/economia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/tendências , Desenvolvimento Econômico/tendências , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Estados Unidos
18.
Value Health ; 22(6): 642-647, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31198180

RESUMO

OBJECTIVE: To explore payer feedback regarding awareness of new gene therapies, sustainability of current financing mechanisms, unique challenges by payer segment, and need and preference for new financial models. STUDY DESIGN: Qualitative interview with standardized interview guide. METHODS: Sixty-minute telephone interviews were conducted with financial decision makers from 15 US payers between August and September 2017. RESULTS: One-third of payers interviewed (n = 5) were newly aware and learning about new gene therapies, 40% (n = 6) described watchful waiting, whereas 26.7% (n = 4) were engaged in active management. New payment models-specifically, performance-based agreements and risk-pooling-were supported by 47% (n = 7) of payers, whereas the current payment model was supported by 53% (n = 8). Major challenges included uncertainty related to utilization, cost, and duration of cure. Payers cited regulation, plan turnover, and ability to track long-term outcomes as barriers to implementation of new models. CONCLUSIONS: Access to new gene therapies may be impacted by payer ability to absorb the cost of coverage. Variation exists in awareness of new gene therapies and level of incorporation of new costs into future plan coverage. The sustainability of current financing mechanisms varies by payer segment, profitability, and size; smaller plans and Medicaid are likely to be impacted first. Government reinsurance, commercial reinsurance, and stop-loss insurance backstop current reimbursement models, dampening the need for urgent action. The tipping point for action may be severe premium inflation in stop loss and reinsurance. Payers are open to innovative financing models that improve financial predictability and reward clinical performance.


Assuntos
Terapia Genética/normas , Acesso aos Serviços de Saúde/normas , Terapia Genética/métodos , Gastos em Saúde/normas , Gastos em Saúde/tendências , Humanos , Entrevistas como Assunto/métodos , Medicaid/organização & administração , Medicare/organização & administração , Pesquisa Qualitativa , Estados Unidos
19.
Expert Rev Clin Pharmacol ; 12(8): 757-770, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31220956

RESUMO

Introduction: Genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood. Recently, advanced technologies have greatly expanded preclinical and clinical research, and specific therapies have been developed. Area covered: We provide an overview of novel pharmacological approaches to the main NMDs, including Duchenne muscular dystrophy (DMD), spina muscular atrophy (SMA), X-linked myotubular myopathy, Pompe disease (PD), and myotonic dystrophy type 1, with attention to both achievements and unresolved therapeutic challenges. We conducted a selected review of relevant publications in the last five years identified through PubMed and Scopus. Additional information was derived from the website of clinicaltrials.gov and from the authors' direct knowledge of research activities. Expert Opinion: For the first time, targeted therapies have received conditional regulatory approval and have been introduced into clinical care: enzyme replacement therapy for PD, gene expression modulation for DMD and SMA, and gene therapy for SMA. Though not curative, these treatments can improve functioning and increase survival. Issues still to be addressed include: early recognition, definition of new emerging phenotypes, development of more sensitive outcome measures, long-term risk-benefit estimates, high costs sustainability, and criteria for therapy initiation and discontinuation.


Assuntos
Terapia Genética/métodos , Terapia de Alvo Molecular , Doenças Neuromusculares/terapia , Animais , Criança , Desenho de Drogas , Humanos , Doenças Neuromusculares/genética , Doenças Neuromusculares/fisiopatologia
20.
Eur J Pharm Biopharm ; 141: 161-171, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150809

RESUMO

Considerable research over the last few years has revealed dysregulation of growth factors in various retinal diseases, such as glaucoma, diabetic retinopathy and photoreceptor degenerations. The use of messengerRNA (mRNA) to transiently overexpress a specific factor could compensate for this imbalance. However, a critical challenge of this approach lies in the ability to efficiently deliver mRNA molecules to the retinal target cells. In this study we found that intravitreal (IVT) injection is an attractive approach to deliver mRNA to the retina, providing two critical barriers can be overcome: the vitreous and the inner limiting membrane (ILM). We demonstrated that the vitreous is indeed a major hurdle in the delivery of the cationic mRNA-complexes to retinal cells, both in terms of vitreal mobility and cellular uptake. To improve their intravitreal mobility and avoid unwanted extracellular interactions, we evaluated the use of hyaluronic acid (HA) as an electrostatic coating strategy. This HA-coating provided the complexes with a negative surface charge, markedly enhancing their mobility in the vitreous humor, without reducing their cellular internalization and transfection efficiency. However, although this coating strategy allows the mRNA-complexes to successfully overcome the vitreal barrier, the majority of the particles accumulated at the ILM. This study therefore underscores the crucial barrier function of the ILM toward non-viral retinal gene delivery and the need to smartly design mRNA-carriers able to surmount the vitreous as well as the ILM.


Assuntos
Ácido Hialurônico/metabolismo , Retina/metabolismo , Animais , Bovinos , Linhagem Celular , Técnicas de Transferência de Genes , Terapia Genética/métodos , Humanos , Injeções Intravítreas/métodos , RNA Mensageiro/metabolismo , Doenças Retinianas/metabolismo , Eletricidade Estática , Transfecção/métodos , Corpo Vítreo/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA