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Latest Articles on Gene Therapy

Overview of latest articles and publications on gene therapy in PubMed, including Human Gene Therapy, Journal of Molecular Medicine and Journal of Gene Medicine. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.


  • Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24(+) patients with renal cell carcinoma.
    Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24(+) patients with renal cell carcinoma. [Journal Article]Int Immunopharmacol 2017 Jan 19.:197-202.IIMinami T, Matsumura N, Sugimoto K, et al. Hypoxic tumor microenvironment makes cancer cells to be therapy-resistant and hypoxia-inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often ...Hypoxic tumor microenvironment makes cancer cells to be therapy-resistant and hypoxia-inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often associated with von Hippel-Lindau (VHL) gene mutations, leading to up-regulation of HIFs. However, from a different point of view, this suggests the possibility that HIFs could be promising targets in anti-cancer therapy. In this study, we searched for HIF-1α-derived peptides that are able to induce RCC-reactive cytotoxic T lymphocytes (CTLs) from HLA-A24(+) RCC patients. Among five peptides derived from HIF-1α, which were prepared based on the binding motif to the HLA-A24 allele, a HIF-1α278-287 peptide induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients most effectively. In immunoblot assays, the expression of HIF-1α was lowly detected in whole and nuclear lysates of RCC cell lines even under normoxia (20% O2), and their expression in whole lysates was increased under hypoxia (1% O2). Additionally, HIF-1α278-287 peptide-stimulated T cells showed a higher cytotoxicity against HLA-A24(+) HIF-1α-expressing RCC cells than against HLA-A24(-) HIF-1α-expressing RCC cells. The cytotoxicity was inhibited by the addition of HIF-1α278-287 peptide-pulsed cold target cells. Altogether, these results indicate that the HIF-1α278-287 peptide could be a candidate for peptide-based anti-cancer vaccines for HLA-A24(+) RCC patients.

  • TGF-β engineered mesenchymal stem cells (TGF-β/MSCs) for treatment of Type 1 diabetes (T1D) mice model.
    TGF-β engineered mesenchymal stem cells (TGF-β/MSCs) for treatment of Type 1 diabetes (T1D) mice model. [Journal Article]Int Immunopharmacol 2017 Jan 19.:191-196.IIDaneshmandi S, Karimi MH, Pourfathollah AA Engineered TGF-β/MSCs could restore some T1D features, including the regulation of adverse immune responses and could be potent tools for cell therapy of T1D comparing MSCs alone.Mesenchymal stem cells (MSCs) are advantageous candidates for cell therapy of Type 1 diabetes (T1D). Considering immunomodulatory effect of MSC, in this study, we engineered MSCs with TGF-β gene to increase MSC potency for T1D therapy in mouse model.Two plans were designed for prevention and treatment of diabetes, respectively. In both of them, MSCs were injected i.v. and then, the diabetes features including serum insulin, blood glucose, glucose tolerance, splenocytes proliferation, and IL-4/IFN-γ production were evaluated.TGF-β/MSCs treatment program resulted in the restoration of serum glucose after 3weeks, while prevention program could delay diabetes progression for two weeks. TGF-β/MSCs treatment elevated the levels of serum insulin and Th2 cytokine shift on 5th week after start of treatment. TGF-β/MSCs (and MSCs alone) could also diminish body weight and enhance mice survival comparing to untreated diabetic mice.Engineered TGF-β/MSCs could restore some T1D features, including the regulation of adverse immune responses and could be potent tools for cell therapy of T1D comparing MSCs alone.

  • Peptide and nucleic acid-directed self-assembly of cationic nanovehicles through giant unilamellar vesicle modification: targetable nanocomplexes for in vivo nucleic acid delivery.
    Peptide and nucleic acid-directed self-assembly of cationic nanovehicles through giant unilamellar vesicle modification: targetable nanocomplexes for in vivo nucleic acid delivery. [Journal Article]Acta Biomater 2017 Jan 18.ABTagalakis AD, Maeshima R, Yu-Wai-Man C, et al. One of the greatest challenges for the development of genetic therapies is the efficient targeted delivery of therapeutic nucleic acids. Towards this goal, we have introduced a new engineering initiati...One of the greatest challenges for the development of genetic therapies is the efficient targeted delivery of therapeutic nucleic acids. Towards this goal, we have introduced a new engineering initiative in self-assembly of biologically safe and stable nanovesicle complexes (∼90-140 nm) derived from giant unilamellar vesicle (GUV) precursors and comprising plasmid DNA or siRNA and targeting peptide ligands. The biological performance of the engineered nanovesicle complexes were studied both in vitro and in vivo and compared with cationic liposome-based lipopolyplexes. Compared with cationic lipopolyplexes, nanovesicle complexes did not show advantages in transfection and cell uptake. However, nanovesicle complexes neither displayed significant cytotoxicity nor activated the complement system, which are advantageous for intravenous injection and tumour therapy. On intravenous administration into a neuroblastoma xenograft mouse model, nanovesicle complexes were found to distribute throughout the tumour interstitium, thus providing an alternative safer approach for future development of tumour-specific therapeutic nucleic acid interventions. On oropharyngeal instillation, nanovesicle complexes displayed better transfection efficiency than cationic lipopolyplexes. The technological advantages of nanovesicle complexes, originating from GUVs, over traditional cationic liposome-based lipopolyplexes are discussed.The efficient targeted delivery of nucleic acids in vivo provides some of the greatest challenges to the development of genetic therapies. Giant unilamellar lipid vesicles (GUVs) have been used mainly as cell and tissue mimics and are instrumental in studying lipid bilayers and interactions. Here, the GUVs have been modified into smaller nanovesicles. We have then developed novel nanovesicle complexes comprising self-assembling mixtures of the nanovesicles, plasmid DNA or siRNA, and targeting peptide ligands. Their biophysical properties were studied and their transfection efficiency was investigated. They transfected cells efficiently without any associated cytotoxicity and with targeting specificity, and in vivo they resulted in very high and tumour-specific uptake and in addition, efficiently transfected the lung. The peptide-targeted nanovesicle complexes allow for the specific targeted enhancement of nucleic acid delivery with improved biosafety over liposomal formulations and represent a promising tool to improve our arsenal of safe, non-viral vectors to deliver therapeutic cargos in a variety of disorders.

  • Activation of dendritic cells by low molecular weight oyster polysaccharides.
    Activation of dendritic cells by low molecular weight oyster polysaccharides. [Journal Article]Int Immunopharmacol 2017 Jan 18.:183-190.IIZhong M, Zhong C, Wang T, et al. Dendritic cells play a primary role in antigen presentation to CD4(+) T cells, which initiate acquired immune responses. Therefore, determining positive modulators of dendritic cell activation to impro...Dendritic cells play a primary role in antigen presentation to CD4(+) T cells, which initiate acquired immune responses. Therefore, determining positive modulators of dendritic cell activation to improve therapeutic approaches for cancer treatment might be useful. We here investigated the effects of low molecular weight oyster polysaccharides (LMW-OPS) on bone marrow-derived dendritic cells (BMDCs) obtained from mice. LMW-OPS increased the surface expression of major histocompatibility complex class II (MHC-II), CD40 and CD86 in BMDCs and induced the secretion of tumour necrosis factor (TNF)-α and interleukin (IL)-12, which were significantly decreased in the BMDCs derived from MyD88(-/-) mice but not from the lipopolysaccharide-resistant C3H/HeJ mice. BMDCs treated with LMW-OPS augmented allogeneic CD4(+) T cell expansion and enhanced secretion of IL-2 and interferon (IFN)-γ but not IL-4. LMW-OPS induced significant increases in ERK and p38 MAPK phosphorylation, but not c-Jun N-terminal kinase (JNK) phosphorylation, in BMDCs. Our results indicate that, in part, LMW-OPS can induce maturation of BMDCs in a MyD88-dependent and Toll-like receptor (TLR) 4-independent manner. LMW-OPS may enhance acquired immunity by modulating the function of dendritic cells.

  • DNA damage response in patients with pediatric Acute Lymphoid Leukemia during induction therapy.
    DNA damage response in patients with pediatric Acute Lymphoid Leukemia during induction therapy. [Journal Article]Leuk Res 2017 Jan 11.:59-65.LRPortich JP, Dos Santos RP, Kersting N, et al. Predicting the individual response to chemotherapy is a crucial challenge in cancer treatment. DNA damage caused by antitumor therapies evokes different repair mechanisms responses, such as Nucleotide ...Predicting the individual response to chemotherapy is a crucial challenge in cancer treatment. DNA damage caused by antitumor therapies evokes different repair mechanisms responses, such as Nucleotide Excision Repair (NER), whose components are being studied as prognosis biomarkers and target therapies. However, few reports have addressed DNA damages in pediatric Acute Lymphoid Leukemia (ALL). Hence, we conducted an observational follow-up study with pediatric patients to assess DNA damage (by Comet Assay) and gene expression from NER pathway during chemotherapy induction. Bone marrow samples from diagnosis, 15th(D15) and 35th (D35) days of the treatment were collected from 28 patients with ALL. There was no increase in damage index. However, there was a reduction of cells with low damages on D35 compared with diagnosis. NER pathway expression remained the same, however, in a single patient, a significant decrease was observed, maybe due to silencing or downregulation of repair pathways. DNA damage levels and repair may influence the clinical outcome, being involved in drug resistance and risk of relapse. In pediatric ALL, we analyzed for the first time DNA damage and repair behavior in BM samples. Monitoring patient's outcomes will help to access the implication of our findings in survival and relapse rates.

  • RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21.
    RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21. [Journal Article]Mol Ther 2017 Jan 18.MTLee TJ, Yoo JY, Shu D, et al. Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust an...Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.

  • CRISPR/Cas9-Mediated Genome Editing as a Therapeutic Approach for Leber Congenital Amaurosis 10.
    CRISPR/Cas9-Mediated Genome Editing as a Therapeutic Approach for Leber Congenital Amaurosis 10. [Journal Article]Mol Ther 2017 Jan 18.MTRuan GX, Barry E, Yu D, et al. As the most common subtype of Leber congenital amaurosis (LCA), LCA10 is a severe retinal dystrophy caused by mutations in the CEP290 gene. The most frequent mutation found in patients with LCA10 is a ...As the most common subtype of Leber congenital amaurosis (LCA), LCA10 is a severe retinal dystrophy caused by mutations in the CEP290 gene. The most frequent mutation found in patients with LCA10 is a deep intronic mutation in CEP290 that generates a cryptic splice donor site. The large size of the CEP290 gene prevents its use in adeno-associated virus (AAV)-mediated gene augmentation therapy. Here, we show that targeted genomic deletion using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system represents a promising therapeutic approach for the treatment of patients with LCA10 bearing the CEP290 splice mutation. We generated a cellular model of LCA10 by introducing the CEP290 splice mutation into 293FT cells and we showed that guide RNA pairs coupled with SpCas9 were highly efficient at removing the intronic splice mutation and restoring the expression of wild-type CEP290. In addition, we demonstrated that a dual AAV system could effectively delete an intronic fragment of the Cep290 gene in the mouse retina. To minimize the immune response to prolonged expression of SpCas9, we developed a self-limiting CRISPR/Cas9 system that minimizes the duration of SpCas9 expression. These results support further studies to determine the therapeutic potential of CRISPR/Cas9-based strategies for the treatment of patients with LCA10.

  • Optical Barcoding for Single-Clone Tracking to Study Tumor Heterogeneity.
    Optical Barcoding for Single-Clone Tracking to Study Tumor Heterogeneity. [Journal Article]Mol Ther 2017 Jan 18.MTMohme M, Maire CL, Riecken K, et al. Intratumoral heterogeneity has been identified as one of the strongest drivers of treatment resistance and tumor recurrence. Therefore, investigating the complex clonal architecture of tumors over time...Intratumoral heterogeneity has been identified as one of the strongest drivers of treatment resistance and tumor recurrence. Therefore, investigating the complex clonal architecture of tumors over time has become a major challenge in cancer research. We developed a new fluorescent "optical barcoding" technique that allows fast tracking, identification, and quantification of live cell clones in vitro and in vivo using flow cytometry (FC). We optically barcoded two cell lines derived from malignant glioma, an exemplary heterogeneous brain tumor. In agreement with mathematical combinatorics, we demonstrate that up to 41 clones can unambiguously be marked using six fluorescent proteins and a maximum of three colors per clone. We show that optical barcoding facilitates sensitive, precise, rapid, and inexpensive analysis of clonal composition kinetics of heterogeneous cell populations by FC. We further assessed the quantitative contribution of multiple clones to glioblastoma growth in vivo and we highlight the potential to recover individual viable cell clones by fluorescence-activated cell sorting. In summary, we demonstrate that optical barcoding is a powerful technique for clonal cell tracking in vitro and in vivo, rendering this approach a potent tool for studying the heterogeneity of complex tissues, in particular, cancer.

  • Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.
    Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. [Journal Article]Eur J Paediatr Neurol 2017 Jan 14.EJvon Stülpnagel C, Ensslen M, Møller RS, et al. Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epileps...To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment.Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire.7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion).Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

  • Langerhans cell markers CD1a and CD207 are the most rapidly responding genes in lesional psoriatic skin following adalimumab treatment.
    Langerhans cell markers CD1a and CD207 are the most rapidly responding genes in lesional psoriatic skin following adalimumab treatment. [Journal Article]Exp Dermatol 2017 Jan 21.EDRaaby L, Rosada C, Langkilde A, et al. TNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin the presence of Langerhans cells ...Publisher Full TextTNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin the presence of Langerhans cells (LC) is reduced, but the role of LC is poorly understood. The purpose of this study was to investigate the impact of TNFα and IL-23/IL-17 on the presence of LC in the skin during treatment. Therefore, psoriatic skin was investigated before and after 4 days of adalimumab or ustekinumab treatment. Furthermore, TNFα and IL-17A stimulation was investigated in an ex vivo model of epidermis and dermis from healthy normal skin kept in cultures at an air-liquid interphase for 4 days. In a gene array analysis we found that the two LC markers, CD1a and CD207, were among the most up- or downregulated genes in psoriatic skin after anti-TNFα therapy. Validation showed that both mRNA expression and protein level followed the same pattern and became significantly upregulated after 4 days of treatment. No changes were seen after ustekinumab treatment. In the ex vivo skin model, a decrease in the CD1a level was seen after TNFα stimulation and it was caused by LC migration from epidermis. No response in LC migration was seen after IL-17A stimulation. Taken together, we demonstrated that changes in the LC level in epidermis precede the histological and clinical changes during adalimumab treatment in psoriatic skin. Furthermore, TNFα plays a prominent role in orchestrating LC migration in the skin. This seems not to be the true for the IL-23/IL-17A pathway. This article is protected by copyright. All rights reserved.

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