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 designed and optimized for induction of antigen-specific immune tolerance. One approach is to specifically express a gene in a tissue with a tolerogenic microenvironment such as the liver or thymus. Another strategy is to transfer a particular gene into hematopoietic stem cells or immunological precursor cells thus educating the immune system to recognize the therapeutic protein as "self". In addition, expression of the therapeutic protein in pro-tolerogenic antigen presenting cells such as immature dendritic cells and B cells has proven to be promising. All three approaches have successfully prevented unwanted immune responses in pre-clinical studies aimed at the treatment of inherited protein deficiencies, e.g. lysosomal storage disorders and hemophilia, and of type I diabetes and multiple sclerosis. In this review we focus on current gene transfer protocols that induce tolerance, including gene delivery vehicles and target tissues, and discuss successes and obstacles in different disease models.
journal_name
Mol Ther Methods Clin Devjournal_title
Molecular therapy. Methods & clinical developmentauthors
Sack BK,Herzog RW,Terhorst C,Markusic DMdoi
10.1038/mtm.2014.13subject
Has Abstractpub_date
2014-04-30 00:00:00pages
14013issn
2329-0501pii
S2329-0501(16)30063-8journal_volume
1pub_type
杂志文章abstract::We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger nucleases (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, g...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章,评审
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更新日期:2020-07-03 00:00:00
abstract::Integration of new DNA into cellular genomes mediates replication of retroviruses and transposons; integration reactions have also been adapted for use in human gene therapy. Tracking the distributions of integration sites is important to characterize populations of transduced cells and to monitor potential outgrow of...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2016.11.002
更新日期:2016-12-18 00:00:00
abstract::The marketing approval of genetically engineered hematopoietic stem cells (HSCs) as the first-line therapy for the treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a tribute to the substantial progress that has been made regarding HSC engineering in the past decade. Rep...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章,评审
doi:10.1016/j.omtm.2017.03.003
更新日期:2017-03-18 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::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::Recombinant adeno-associated virus (rAAV) vectors are considered ideal vehicles for human gene therapy. Meanwhile, non-viral strategies, such as transfection agents (TAs), have also shown promise to deliver genetic materials, such as siRNA. Transduction with the rAAV vector is performed concurrently with transfection ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.04.004
更新日期:2018-04-12 00:00:00
abstract::Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2016.12.004
更新日期:2016-12-24 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::Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive muscle weakness. The disease is caused by mutations in the acid α-glucosidase (GAA) gene. Despite the currently available enzyme replacement therapy (ERT), roughly half of the infants with Pompe disease die before the age o...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.04.023
更新日期:2020-05-04 00:00:00
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journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.05.010
更新日期:2020-05-22 00:00:00
abstract::In vivo imaging of vector transgene expression would be particularly valuable for repetitive monitoring of therapy in the brain, where invasive tissue sampling is contraindicated. We evaluated adeno-associated virus vector expression of a dopamine-2 receptor (D2R) mutant (D2R80A) by positron emission tomography in the...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2014.16
更新日期:2014-06-04 00:00:00
abstract::Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.12.002
更新日期:2019-12-14 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::Pompe disease (PD) is a lysosomal disorder caused by acid α-glucosidase (GAA) deficiency. Progressive muscular weakness is the major symptom of PD, and enzyme replacement therapy can improve the clinical outcome. However, to achieve a better clinical outcome, alternative therapeutic strategies are being investigated, ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.54
更新日期:2016-08-10 00:00:00
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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::Adeno-associated virus (AAV) vectors have become one of the most widely used gene transfer tools in human gene therapy. Considerable effort is currently being focused on AAV capsid engineering strategies with the aim of developing novel variants with enhanced tropism for specific human cell types, decreased human sero...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.10.016
更新日期:2018-11-01 00:00:00
abstract::New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity1 has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a consti...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2017.08.007
更新日期:2017-09-07 00:00:00
abstract::Gene therapy has been shown to be a feasible approach to treat inherited disorders in vivo. Among the currently used viral vector systems, adeno-associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of exp...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.02.010
更新日期:2018-02-27 00:00:00
abstract::Adeno-associated viruses (AAVs) are the vector of choice for gene therapy in the eye, and self-complementary AAVs (scAAVs), which do not require second-strand DNA synthesis, can be transduced into cells of the trabecular meshwork (TM). The scAAV transduction patterns in the anterior segment of normotensive eyes have b...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2019.06.009
更新日期:2019-07-10 00:00:00
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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
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journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1038/mtm.2016.57
更新日期:2016-08-24 00:00:00
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journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.10.009
更新日期:2020-10-20 00:00:00
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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 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::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
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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::Adoptive natural killer (NK) cell therapy is attaining promising clinical outcomes in recent years, but improvements are needed. Genetic modification of NK cells with a tumor antigen-specific receptor on their surface coupled to intracellular signaling domains may lead to enhanced cytotoxicity against malignant cells....
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2020.03.017
更新日期:2020-03-29 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::Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.10.012
更新日期:2018-12-05 00:00:00
abstract::Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene (SMN1), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic ...
journal_title:Molecular therapy. Methods & clinical development
pub_type: 杂志文章
doi:10.1016/j.omtm.2018.01.007
更新日期:2018-01-31 00:00:00