Abstract:
:Preventing untoward immune responses against a specific antigen is a major challenge in different clinical settings such as gene therapy, transplantation, or autoimmunity. Following intramuscular delivery of recombinant adeno-associated virus (rAAV)-derived vectors, transgene rejection can be a roadblock to successful clinical translation. Specific immunomodulation strategies potentially leading to sustained transgene expression while minimizing pharmacological immunosuppression are desirable. Tolerogenic dendritic cells (TolDC) are potential candidates but have not yet been evaluated in the context of gene therapy, to our knowledge. Following intramuscular delivery of rAAV-derived vectors expressing an immunogenic protein in the nonhuman primate model, we assessed the immunomodulating potential of autologous bone marrow-derived TolDC generated in the presence of IL10 and pulsed with the transgene product. TolDC administered either intradermally or intravenously were safe and well tolerated. While the intravenous route showed a modest ability to modulate host immunity against the transgene product, intradermally delivery resulted in a robust vaccination of the macaques when associated to intramuscular rAAV-derived vectors-based gene transfer. These findings demonstrate the critical role of TolDC mode of injection in modulating host immunity. This study also provides the first evidence of the potential of TolDC-based immunomodulation in gene therapy.
journal_name
Mol Ther Methods Clin Devjournal_title
Molecular therapy. Methods & clinical developmentauthors
Moreau A,Vandamme C,Segovia M,Devaux M,Guilbaud M,Tilly G,Jaulin N,Le Duff J,Cherel Y,Deschamps JY,Anegon I,Moullier P,Cuturi MC,Adjali Odoi
10.1038/mtm.2014.28subject
Has Abstractpub_date
2014-07-23 00:00:00pages
14028issn
2329-0501pii
S2329-0501(16)30094-8journal_volume
1pub_type
杂志文章abstract::Gene transfer to and correction of hematopoietic stem cells (HSCs) are ideal strategies to cure a number of congenital and acquired disorders. However, transgene products may trigger immunological rejection of modified cells, limiting their therapeutic benefits. Preclinical and clinical data indicate that myeloablativ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章,评审
doi:10.1016/j.omtm.2019.10.010
更新日期:2019-10-31 00:00:00
abstract::Recombinant adeno-associated virus (rAAV) is one of the main vectors used in gene therapy. An accurate genome titer is not only critical for clinical dosing, but also a prerequisite for many analytical assays for AAV product characterization. AAV genome titer is traditionally determined by qPCR; however, assay precisi...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.09.017
更新日期:2020-10-01 00:00:00
abstract::Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.13
更新日期:2016-03-30 00:00:00
abstract::Current cell processing technologies for gene and cell therapies are often slow, expensive, labor intensive and are compromised by high cell losses and poor selectivity thus limiting the efficacy and availability of clinical cell therapies. We employ cell-specific on-demand mechanical intracellular impact from laser p...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.12
更新日期:2016-03-16 00:00:00
abstract::Validation of gene transfer vectors containing tissue-specific promoters in cell-based functional assays poses a formidable challenge for gene therapy product development. Here, we describe a novel approach based on CRISPR/dCas9 transcriptional activation to achieve robust transgene expression from transgene cassettes...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.03.004
更新日期:2019-03-28 00:00:00
abstract::Hypoxic regions within the tumor form due to imbalances between cell proliferation and angiogenesis; specifically, temporary closure or a reduced flow due to abnormal vasculature. They create environments where cancer cells acquire resistance to therapies. Therefore, the development of therapeutic approaches targeting...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.9
更新日期:2016-03-02 00:00:00
abstract::Gene therapy has been suggested as a plausible novel approach to achieve seizure control in patients with focal epilepsy that do not adequately respond to pharmacological treatment. We investigated the seizure-suppressant potential of combinatorial neuropeptide Y and Y2 receptor single vector gene therapy based on ade...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.09.004
更新日期:2019-09-18 00:00:00
abstract::The delivery of factor VIII (FVIII) through gene and/or cellular platforms has emerged as a promising hemophilia A treatment. Herein, we investigated the suitability of human placental cells (PLCs) as delivery vehicles for FVIII and determined an optimal FVIII transgene to produce/secrete therapeutic FVIII levels from...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.03.001
更新日期:2020-03-14 00:00:00
abstract::To date, gene therapy with transiently derived lentivectors has been very successful to cure rare infant genetic diseases. However, transient manufacturing is unfeasible to treat adult malignancies because large vector lots are required. By contrast, stable manufacturing is the best option for high-incidence diseases ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.33
更新日期:2016-05-11 00:00:00
abstract::The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.83
更新日期:2016-12-07 00:00:00
abstract::Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2 (-/-) ) mice, which mimic the phenotype of the severe infantile ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2015.59
更新日期:2016-02-03 00:00:00
abstract::Possible risks and lack of donor livers limit application of liver transplantation. Liver cell transplantation is, at this moment, not a feasible alternative because engraftment in the liver is poor. Furthermore, there is also shortage of cells suitable for transplantation. Fetal liver cells are able to proliferate in...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2014.3
更新日期:2014-03-12 00:00:00
abstract::rAAVrh74.MCK.GALGT2 is a surrogate gene therapy that inhibits muscular dystrophy in multiple animal models. Here, we report on a dose-response study of functional muscle GALGT2 expression as well as toxicity and biodistribution studies after systemic intravenous (i.v.) delivery of rAAVrh74.MCK.GALGT2. A dose of 4.3 × ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.10.005
更新日期:2019-10-21 00:00:00
abstract::Exudative age-related macular degeneration (AMD), characterized by choroidal neovascularization (CNV), is the leading cause of irreversible blindness in developed countries. Anti-vascular endothelial growth factor (VEGF) drugs are the standard treatment for AMD, but they have limitations. Cell therapy is a promising a...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.05.007
更新日期:2019-05-22 00:00:00
abstract::Insertional mutagenesis has been associated with malignant cell transformation in gene therapy protocols, leading to discussions about vector security. Therefore, clonal analysis is important for the assessment of vector safety and its impact on patient health. Here, we report a unique approach to assess dynamic chang...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2014.52
更新日期:2014-11-19 00:00:00
abstract::Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB [MPS IIIB]) is a lysosomal storage disorder primarily affecting the brain that is caused by a deficiency in the enzyme α-N-acetylglucosaminidase (NAGLU), leading to intralysosomal accumulation of heparan sulfate. There are currently no treatments for this dis...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.06.005
更新日期:2018-07-23 00:00:00
abstract::Herpes simplex keratitis (HSK) is the most common cause of corneal blindness in developed nations, caused by primary or recurrent herpes simplex virus 1 (HSV-1) infection of the cornea. Latent infection of HSV-1, especially in the trigeminal ganglion (TG), causes recurrence of HSV-1 infection. As antiviral treatment i...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.05.011
更新日期:2020-05-22 00:00:00
abstract::Retroviral vectors, including those derived from gammaretroviruses and lentiviruses, have found their way into the clinical arena and demonstrated remarkable efficacy for the treatment of immunodeficiencies, leukodystrophies, and globinopathies. Despite these successes, gene therapy unfortunately also has had to face ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章,评审
doi:10.1016/j.omtm.2017.10.002
更新日期:2017-10-05 00:00:00
abstract::[This corrects the article DOI: 10.1038/mtm.2015.16.]. ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 已发布勘误
doi:10.1038/mtm.2016.32
更新日期:2016-05-25 00:00:00
abstract::The overall goal of our research is to establish a preformed molecular guidance pathway to direct the growth of dopaminergic axons from embryonic ventral mesencephalon (VM), tissue placed within the substantia nigra (SN), into the striatum to reconstruct the nigrostriatal pathway in a hemi-Parkinson's disease rat mode...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.06.008
更新日期:2019-07-11 00:00:00
abstract::Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that influence AAV distrib...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.04.012
更新日期:2020-04-18 00:00:00
abstract::Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR) has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2014.61
更新日期:2015-04-01 00:00:00
abstract::Gene replacement therapies, like organ and cell transplantation are likely to introduce neo-antigens that elicit rejection via humoral and/or effector T cell immune responses. Nonetheless, thanks to an ever growing body of pre-clinical studies it is now well accepted that gene transfer protocols can be specifically de...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2014.13
更新日期:2014-04-30 00:00:00
abstract::Methods for customizing and improving virus vector tropism are limited. In this study, we introduce a microRNA (miRNA)-regulated molecular method to enhance vector transduction without genome alteration. Based on the importance of adenovirus (Ad) vectors for cancer and gene treatment, we exemplified this technology fo...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.06.010
更新日期:2020-06-18 00:00:00
abstract::Identification and characterization of disease-associated variants in monogenic disorders is an important aspect of diagnosis, genetic counseling, prediction of disease severity, and development of therapy. However, the effects of disease-associated variants on pre-mRNA splicing and mRNA degradation are difficult to p...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.09.004
更新日期:2020-09-16 00:00:00
abstract::The tuberculosis (TB) vaccine MTBVAC is the only live-attenuated Mycobacterium tuberculosis (Mtb)-based vaccine in clinical development, and it confers superior protection in different animal models compared to the current vaccine, BCG (Mycobacterium bovis bacillus Calmette-Guérin). With the aim of using MTBVAC as a v...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.01.014
更新日期:2019-02-07 00:00:00
abstract::LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associat...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.01.005
更新日期:2018-01-31 00:00:00
abstract::Adeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene e...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.05.033
更新日期:2020-06-02 00:00:00
abstract::Recombinant adeno-associated virus (rAAV)rh74.MCK.GALGT2 is a muscle-specific gene therapy that is being developed to treat forms of muscular dystrophy. Here we report on an isolated limb infusion technique in a non-human primate model, where hindlimb blood flow is transiently isolated using balloon catheters to conce...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.06.002
更新日期:2018-07-14 00:00:00
abstract::Vaccinia virus (VACV) was successfully used as a vaccine in the smallpox eradication campaign. Since then, it has been widely used in the development of vaccine and therapeutic vectors. However, methods of generating and purifying recombinant VACVs (rVACVs) are often time-consuming, cumbersome, and in some cases requi...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.03.026
更新日期:2020-03-30 00:00:00