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2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(4): 540-545, 2020 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895108

RESUMO

Ultrasound contrast agent microbubbles combined with low frequency ultrasound named as low-frequency ultrasound-targeted microbubble destruction technology has become an effective and non-invasive anti-tumor therapy for deep tumors.It can enhance the efficacies of chemotherapy,gene therapy,immunotherapy,and anti-angiogenic therapy by improving cell membrane permeability and destroying tumor neovasculature.It can be applied to sonodynamic therapy and realize multimodal synergistic therapy on the basis of nanoparticles,which increases the anti-tumor efficiency and offers a promising target therapy for tumors.


Assuntos
Microbolhas , Neoplasias , Meios de Contraste , Terapia Genética , Humanos , Ultrassonografia
3.
Value Health ; 23(9): 1268-1280, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32940245

RESUMO

OBJECTIVES: To identify methodological considerations discussed in literature addressing economic evaluations (EEs) of gene therapies (GTs). Additionally, we assessed if these considerations are applied in published GT EEs to increase understanding and explore impact. METHODS: First a peer-reviewed literature review was performed to identify research addressing methodological considerations of GT EEs until August 2019. Identified considerations were grouped in themes using thematic content analysis. A second literature search was conducted in which we identified published evaluations. The EE quality of reporting was assessed using Consolidated Health Economic Evaluation Reporting Standards. RESULTS: The first literature search yielded 13 articles discussing methodological considerations. The second search provided 12 EEs. Considerations identified were payment models, definition of perspectives, addressing uncertainty, data extrapolation, discount rates, novel value elements, and use of indirect and surrogate endpoints. All EEs scored satisfactory to good according to Consolidated Health Economic Evaluation Reporting Standards. Regarding methodological application, we found 1 methodological element (payment models) was applied in 2 base cases. Scenarios explored alternative perspectives, survival assumptions, and extrapolation methods in 10 EEs. CONCLUSIONS: Although EE quality of reporting was considered good, their informativeness for health technology assessment and decision makers seemed limited owing to many uncertainties. We suggest accepted EE methods can broadly be applied to GTs, but few elements may need adjustment. Further research and multi-stakeholder consensus is needed to determine appropriateness and application of individual methodological considerations. For now, we recommend including scenario analyses to explore impact of methodological choices and (clinical) uncertainties. This study contributes to better understanding of perceived appropriate evaluation of GTs and informs best modeling practices.


Assuntos
Terapia Genética/economia , Modelos Econômicos , Análise Custo-Benefício , Estudos de Avaliação como Assunto , Humanos
4.
Int J Nanomedicine ; 15: 6183-6200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922001

RESUMO

Purpose: Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. Methods: An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE12-CH-PEG-FA2/siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Results: Our results show that a targeted theoretical plasma concentration (TPC) of DEAE12-CH-PEG-FA2/siRNA nanoparticles falls within the guidelines' thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1ß and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. Conclusion: These DEAE12-CH-PEG-FA2/siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines' threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.


Assuntos
Quitosana/química , Terapia Genética , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade
5.
Kidney Blood Press Res ; 45(5): 661-670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957112

RESUMO

BACKGROUND: The outbreak of severe acute respiratory syndrome ß-coronavirus 2 (SARS-CoV-2) has the potential to become a long-lasting global health crisis. The number of people infected with the novel coronavirus has surpassed 22 million globally, resulting in over 700,000 deaths with more than 15 million people having recovered (https://covid19.who.int). Enormous efforts are underway for rapid vaccine and treatment developments. Amongst the many ways of tackling the novel coronavirus disease 2019 (COVID-19) pandemic, extracellular vesicles (EVs) are emerging. SUMMARY: EVs are lipid bilayer-enclosed structures secreted from all types of cells, including those lining the respiratory tract. They have established roles in lung immunity and are involved in the pathogenesis of various lung diseases, including viral infection. In this review, we point out the roles and possible contribution of EVs in viral infections, as well as ongoing EV-based approaches for the treatment of COVID-19, including clinical trials. Key Messages: EVs share structural similarities to viruses and recent findings demonstrate that viruses exploit EVs for cellular exit and EVs exploit viral entry mechanisms for cargo delivery. Moreover, EV-virus interplay could be exploited for future antiviral drug and vaccine development. EV-based therapies, especially the mesenchymal stem cell-derived EVs, are being intensively studied for the treatment of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Vesículas Extracelulares/virologia , Pneumopatias/terapia , Pneumonia Viral/terapia , Antivirais/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Vesículas Extracelulares/metabolismo , Terapia Genética/tendências , Humanos , Pneumopatias/metabolismo , Pneumopatias/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/fisiologia
6.
Gene ; 763: 145066, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827686

RESUMO

Diabetes is characterized by changed homeostasis of blood glucose levels, which is associated with various complications, including cardiomyopathy, atherosclerosis, endothelial dysfunction, nephropathy, retinopathy and neuropathy. In recent years, accumulative evidence has demonstrated that circular RNAs are identified as a novel type of noncoding RNAs (ncRNAs) involving in the regulation of various physiological processes and pathologic conditions. Specifically, the emergence of complications response to diabetes is finely controlled by a complex gene regulatory network in which circular RNAs play a critical role. Recently, circular RNAs are emerging as messengers that could influence cellular functions under diabetic conditions. Dysregulation of circular RNAs has been closely linked to the pathophysiology of diabetes-related complications. In this review, we aimed to summarize the current progression and underlying mechanisms of circular RNA in the development of diabetes-related complications. We will also provide an overview of circular RNA-regulated cell communications in different types of cells that have been linked to diabetic complications. We anticipated that the completion of this review will provide potential clues for developing novel circular RNAs-based biomarkers or therapeutic targets for diabetes and its associated complications.


Assuntos
Angiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Neuropatias Diabéticas/metabolismo , RNA Circular/metabolismo , Animais , Biomarcadores/metabolismo , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/terapia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/terapia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/terapia , Terapia Genética/métodos , Humanos , Ilhotas Pancreáticas/metabolismo , RNA Circular/genética
7.
Med Sci (Paris) ; 36(8-9): 725-734, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32821049

RESUMO

The prognosis for phenylketonuria (PKU) has been improved by neonatal screening and dietary management via a low-phenylalanine diet. This treatment must be followed throughout life, which induces severe compliance problems. Drug treatment with sapropterin (or BH4) has come to help a reduced percentage of patients who respond to this drug. A subcutaneous enzyme therapy is available in the USA and has obtained European marketing authorization, but generates significant side effects, which limits its effectiveness. New therapeutic options for PKU are currently being developed, in particular gene therapy. The purpose of this article is to take stock of the pathophysiology and the various new therapeutic modalities currently in development.


Assuntos
Dieta , Terapia Genética , Fenilcetonúrias/terapia , Biopterina/análogos & derivados , Biopterina/uso terapêutico , Dieta/efeitos adversos , Dieta/métodos , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Recém-Nascido , Triagem Neonatal , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/dietoterapia , Prognóstico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
8.
Nat Commun ; 11(1): 3929, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764559

RESUMO

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.


Assuntos
Terapia Genética/métodos , Vetores Genéticos , Parvovirinae/genética , Proteinose Alveolar Pulmonar/congênito , Proteína B Associada a Surfactante Pulmonar/deficiência , Animais , Animais Recém-Nascidos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Precursores de Proteínas/genética , Proteolipídeos/genética , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Proteinose Alveolar Pulmonar/terapia , Proteína B Associada a Surfactante Pulmonar/genética , Proteína B Associada a Surfactante Pulmonar/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/genética , Transdução Genética
9.
Am J Bioeth ; 20(8): 7-18, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32757931

RESUMO

The distinction between germline and somatic gene editing is fundamental to the ethics of human gene editing. Multiple conferences of scientists, ethicists, and policymakers, and multiple professional bodies, have called for moratoria on germline gene editing, and editing of human germline cells is considered to be an ethical "red line" that either never should be crossed, or should only be crossed with great caution and care. However, as research on germline gene editing has progressed, it has become clear that not all germline interventions are alike, and that these differences make a significant moral difference, when it comes to ethical questions about research, regulation, clinical application, and medical justification. In this paper, I argue that, rather than lumping all germline interventions together, we should distinguish between revising, correcting, and transferring genes, and I assess the consequences of this move for the ethics of gene editing.


Assuntos
Edição de Genes/ética , Terapia Genética/ética , Células Germinativas , Ética Clínica , Ética em Pesquisa , Humanos , Princípios Morais , Políticas
10.
PLoS One ; 15(8): e0237156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780756

RESUMO

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.


Assuntos
Terapia Genética/métodos , Fator de Crescimento de Hepatócito/genética , Neuralgia/terapia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Hiperalgesia/metabolismo , Lipossomos/metabolismo , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Vírus Sendai/genética , Resultado do Tratamento
11.
Life Sci ; 259: 118165, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735884

RESUMO

CRISPR (clustered regularly interspaced short palindromic Repeats)/Cas9 is a new genetic editing technology that can be a beneficial method to advance gene therapy. CRISPR technology is a defense system of some bacteria against invading viruses. Genome editing based on the CRISPR/Cas9 system is an efficient and potential technology that can be a viable alternative to traditional methods. This system is a compound of a short guide RNAs (gRNAs) for identifying the target DNA sequence and Cas9 protein as nuclease for breaking and cutting of DNA. In this review, recent advances in the CRISPR/Cas9-mediated genome editing tools are presented as well as their use in gene therapy strategies for the treatment of neurological disorders including Parkinson's disease, Alzheimer's disease, and Huntington's disease.


Assuntos
Sistemas CRISPR-Cas , Terapia Genética/métodos , Doenças Neurodegenerativas/terapia , Animais , Humanos
12.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32843442

RESUMO

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.


Assuntos
Terapia Genética/métodos , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/terapia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Adenovírus Humanos , Fatores Etários , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Terapia Genética/efeitos adversos , Vetores Genéticos/administração & dosagem , Glucocorticoides/administração & dosagem , Humanos , Lactente , Ohio , Avaliação de Resultados em Cuidados de Saúde , Prednisolona/administração & dosagem , gama-Glutamiltransferase/metabolismo
13.
Nat Commun ; 11(1): 4034, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788576

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.


Assuntos
Edição de Genes , Terapia Genética , Células-Tronco Hematopoéticas/metabolismo , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Animais , Plaquetas/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem da Célula , Códon/genética , Feminino , Loci Gênicos , Células HEK293 , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Testes de Mutagenicidade , Células Mieloides/metabolismo , Linfócitos T/metabolismo , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/genética
14.
Anticancer Res ; 40(8): 4425-4444, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727773

RESUMO

BACKGROUND/AIM: Patients with metastasized melanoma have limited treatment options and poor diagnosis. Therefore, the development of treatments requires a new therapeutic approach, of which gene therapy using rAAV vectors can be proposed. The aim of the study was to examine the efficiency of the rAAV vector to transduce mouse melanoma cells both in vitro and in vivo. MATERIALS AND METHODS: Different rAAV serotypes encoding GFP under the control of both chicken beta-actin and cytomegalovirus promoters were used in the experiments. Intranasal, intraperitoneal, intravenous and intratumoral pathways of administration of rAAV vectors were tested using quantitative-PCR and immunohistochemical staining. RESULTS: The highest transduction efficiency in metastatic cells in vivo was observed 7 days after intranasal administration of a 1010 gc/0.03 ml dose of rAAV/DJ-CAG. CONCLUSION: Melanoma gene therapy based on rAAV vectors is a possible treatment option.


Assuntos
Dependovirus/genética , Proteínas de Fluorescência Verde/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Melanoma Experimental/genética , Administração Intranasal , Animais , Linhagem Celular Tumoral , Feminino , Terapia Genética , Vetores Genéticos/administração & dosagem , Neoplasias Pulmonares/terapia , Masculino , Melanoma Experimental/terapia , Camundongos , Células NIH 3T3 , Regiões Promotoras Genéticas , Transdução Genética , Resultado do Tratamento
15.
Rev Cardiovasc Med ; 21(2): 163-179, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706206

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão Arterial Pulmonar/terapia , Artéria Pulmonar/efeitos dos fármacos , Animais , Terapia Genética , Humanos , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/mortalidade , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Transplante de Células-Tronco , Resultado do Tratamento
16.
PLoS Comput Biol ; 16(7): e1007857, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32667921

RESUMO

In many cases of inherited retinal degenerations, ganglion cells are spared despite photoreceptor cell death, making it possible to stimulate them to restore visual function. Several studies have shown that it is possible to express an optogenetic protein in ganglion cells and make them light sensitive, a promising strategy to restore vision. However the spatial resolution of optogenetically-reactivated retinas has rarely been measured, especially in the primate. Since the optogenetic protein is also expressed in axons, it is unclear if these neurons will only be sensitive to the stimulation of a small region covering their somas and dendrites, or if they will also respond to any stimulation overlapping with their axon, dramatically impairing spatial resolution. Here we recorded responses of mouse and macaque retinas to random checkerboard patterns following an in vivo optogenetic therapy. We show that optogenetically activated ganglion cells are each sensitive to a small region of visual space. A simple model based on this small receptive field predicted accurately their responses to complex stimuli. From this model, we simulated how the entire population of light sensitive ganglion cells would respond to letters of different sizes. We then estimated the maximal acuity expected by a patient, assuming it could make an optimal use of the information delivered by this reactivated retina. The obtained acuity is above the limit of legal blindness. Our model also makes interesting predictions on how acuity might vary upon changing the therapeutic strategy, assuming an optimal use of the information present in the retinal activity. Optogenetic therapy could thus potentially lead to high resolution vision, under conditions that our model helps to determinine.


Assuntos
Cegueira , Optogenética/métodos , Células Ganglionares da Retina/fisiologia , Animais , Cegueira/fisiopatologia , Cegueira/terapia , Terapia Genética , Macaca , Camundongos , Modelos Biológicos , Retina/fisiologia , Acuidade Visual/fisiologia
17.
N Engl J Med ; 383(2): 151-158, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640133

RESUMO

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.


Assuntos
Esclerose Amiotrófica Lateral/terapia , MicroRNAs/uso terapêutico , Superóxido Dismutase-1/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/genética , Dependovirus , Evolução Fatal , Inativação Gênica , Terapia Genética , Vetores Genéticos , Humanos , Injeções Espinhais , Masculino , Meningoencefalite , Pessoa de Meia-Idade , Mutação , Estudo de Prova de Conceito , Medula Espinal/química , Medula Espinal/patologia , Superóxido Dismutase-1/análise , Superóxido Dismutase-1/genética , Capacidade Vital , Adulto Jovem
18.
Nat Rev Drug Discov ; 19(7): 463-479, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612263

RESUMO

Naturally occurring stem cells isolated from humans have been used therapeutically for decades. This has primarily involved the transplantation of primary cells such as haematopoietic and mesenchymal stem cells and, more recently, derivatives of pluripotent stem cells. However, the advent of cell-engineering approaches is ushering in a new generation of stem cell-based therapies, greatly expanding their therapeutic utility. These next-generation stem cells are being used as 'Trojan horses' to improve the delivery of drugs and oncolytic viruses to intractable tumours and are also being engineered with angiogenic, neurotrophic and anti-inflammatory molecules to accelerate the repair of injured or diseased tissues. Moreover, gene therapy and gene editing technologies are being used to create stem cell derivatives with improved functionality, specificity and responsiveness compared with their natural counterparts. Here, we review these engineering approaches and areas in which they will help broaden the utility and clinical applicability of stem cells.


Assuntos
Engenharia Celular/métodos , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Animais , Sistemas de Liberação de Medicamentos , Edição de Genes , Terapia Genética/métodos , Humanos , Terapia Viral Oncolítica/métodos
20.
Med Sci (Paris) ; 36(6-7): 607-615, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32614312

RESUMO

Retinitis pigmentosa is the most common blinding inherited retinal dystrophy. Gene therapy is a burgeoning revolutionary approach that paves the way to treatment of previously incurable diseases. At the end of 2017 and 2018, a gene therapy, Luxturna®, obtained a marketing authorization by respectively the FDA (Food and Drug Administration) and the EMA (European Medicines Agency). This treatment, with proven efficacy, is available to patients with Leber congenital amaurosis and retinitis pigmentosa associated with bi-allelic mutations of the RPE 65 gene. In this paper, we present the current advances in gene therapy for retinitis pigmentosa and discuss the technological, economic and ethical challenges to overcome for gene therapy to improve medical practices.


Assuntos
Terapia Genética , Retinite Pigmentosa/terapia , Estudos de Associação Genética , Terapia Genética/economia , Terapia Genética/ética , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Mutação , Padrões de Prática Médica/normas , Padrões de Prática Médica/tendências , Melhoria de Qualidade , Retinite Pigmentosa/genética
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