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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.


  • Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy.
    Stockman A, Henning B, Ripamonti C Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy. [Journal Article]J Vis 2015 Sep 1; 15(12):24.AbstractPublisher Full TextRod visual function can be established with some certainty by demonstrating that dark-adapted visual spectral sensitivity has the shape of the rod (scotopic) spectral sensitivity function and that this scotopic shape collapses to a cone (photopic) shape when cones, but not rods, have recovered following an intense bleach. We used these tests to assess retinal function in eight young adult and child patients with early-onset severe retinal dystrophy enrolled in phase II of a clinical gene therapy trial for RPE65 deficiency, an isomerase, the lack of which disrupts the "visual cycle" upon which rods solely depend for regenerating visual pigment after light exposure. The trial involved subretinal delivery of a recombinant adeno-associated viral vector expressing RPE65. After gene therapy, substantial improvements in 1-Hz dark-adapted flicker sensitivity were found in two of the eight patients. One patient showed up to a 1000-fold improvement in sensitivity 4 months after treatment, and the second, up to a 100-fold improvement 6 months after treatment. In both cases, the spectral sensitivity after treatment was rod-like after normal periods of dark adaptation, but remained cone-like during the cone plateau after an intense bleach. The dark-adapted spectral sensitivities of the other six patients were cone-like both before and after treatment with only minimal sensitivity changes. It is not clear why restored rod function was evident in only some patients, but the response may be limited by the extent of retinal degeneration at the locus tested. Meeting abstract presented at VSS 2015.

  • Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells.
    Gérard X, Perrault I, Munnich A, et al. Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells. [Journal Article]Mol Ther Nucleic Acids 2015.:e250.AbstractPublisher Full TextLeber congenital amaurosis is a severe hereditary retinal dystrophy responsible for neonatal blindness. The most common disease-causing mutation (c.2991+1655A>G; 10-15%) creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. Recently, we reported that splice-switching oligonucleotides (SSO) allow skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients, supporting the feasibility of a SSO-mediated exon skipping strategy to correct the aberrant splicing. Here, we present data in the wild-type mouse, which demonstrate that intravitreal administration of 2'-OMePS-SSO allows selective alteration of Cep290 splicing in retinal cells, including photoreceptors as shown by successful alteration of Abca4 splicing using the same approach. We show that both SSOs and Cep290 skipped mRNA were detectable for at least 1 month and that intravitreal administration of oligonucleotides did not provoke any serious adverse event. These data suggest that intravitreal injections of SSO should be considered to bypass protein truncation resulting from the c.2991+1655A>G mutation as well as other truncating mutations in genes which like CEP290 or ABCA4 have a mRNA size that exceed cargo capacities of US Food and Drug Administration (FDA)-approved adeno-associated virus (AAV)-vectors, thus hampering gene augmentation therapy.

  • Effective Small Interfering RNA Therapy to Treat CLCN7-dependent Autosomal Dominant Osteopetrosis Type 2.
    Capulli M, Maurizi A, Ventura L, et al. Effective Small Interfering RNA Therapy to Treat CLCN7-dependent Autosomal Dominant Osteopetrosis Type 2. [Journal Article]Mol Ther Nucleic Acids 2015.:e248.AbstractPublisher Full TextIn about 70% of patients affected by autosomal dominant osteopetrosis type 2 (ADO2), osteoclast activity is reduced by heterozygous mutations of the CLCN7 gene, encoding the ClC-7 chloride/hydrogen antiporter. CLCN7(G215R)-, CLCN7(R767W)-, and CLCN7(R286W)-specific siRNAs silenced transfected mutant mRNA/EGFP in HEK293 cells, in RAW264.7 cells and in human osteoclasts, with no change of CLCN7(WT) mRNA and no effect of scrambled siRNA on the mutant transcripts. Osteoclasts from Clcn7(G213R) ADO2 mice showed reduced bone resorption, a condition rescued by Clcn7(G213R)-specific siRNA. Treatment of ADO2 mice with Clcn7(G213R)-specific siRNA induced increase of bone resorption variables and decrease of trabecular bone mass, leading to an overall improvement of the osteopetrotic bone phenotype. Treatment did not induce overt adverse effects and was effective also with siRNAs specific for other mutants. These results demonstrate that a siRNA-based experimental treatment of ADO2 is feasible, and underscore a translational impact for future strategy to cure this therapeutically neglected form of osteopetrosis.

  • Prolyl hydroxylase inhibitors act as agents to enhance the efficiency of cell therapy.
    Esfahani M, Karimi F, Afshar S, et al. Prolyl hydroxylase inhibitors act as agents to enhance the efficiency of cell therapy. [JOURNAL ARTICLE]Expert Opin Biol Ther 2015 Sep 1.:1-17.AbstractPublisher Full TextIn stem cell-based therapy as a subtype of regenerative medicine, stem cells can be used to replace or repair injured tissue and cells in order to treat disease. Stem cells have the ability to integrate into injured areas and produce new cells via processes of proliferation and differentiation. Several studies have demonstrated that hypoxia increases self-renewal, proliferation and post-homing differentiation of stem cells through the regulation of hypoxia-inducible factor-1 (HIF-1)-mediated gene expression. Thus, pharmacological interventions including prolyl hydroxylase (PHD) inhibitors are considered as promising solutions for stem cell-based therapy. PHD inhibitors stabilize the HIF-1 and activate its pathway through preventing proteasomal degradation of HIF-1. Areas covered: This review focuses on the role of hypoxia, HIF-1 and especially PHD inhibitors on cell therapy. PHD structure and function are discussed as well as their inhibitors. In addition, we have investigated several preclinical studies in which PHD inhibitors improved the efficiency of cell-based therapies. Expert opinion: The data reviewed here suggest that PHD inhibitors are effective operators in improving stem cell therapy. However, because of some limitations, these compounds should be properly examined before clinical application.

  • Magnetic albumin immuno-nanospheres as an efficient gene delivery system for a potential use in lung cancer: preparation, in vitro targeting and biological effect analysis.
    Hou X, Zhang H, Li H, et al. Magnetic albumin immuno-nanospheres as an efficient gene delivery system for a potential use in lung cancer: preparation, in vitro targeting and biological effect analysis. [JOURNAL ARTICLE]J Drug Target 2015 Jul 31.:1-10.AbstractPublisher Full TextMagnetic albumin immuno-nanospheres (MAINs), simultaneously loaded with super-paramagnetic iron oxide nanoparticles for targeting application and anticancer gene, plasmid-survivin/shRNA (pshRNA) and modified with anti-EGFR monoclonal antibody Cetuximab for targeting and treatment agents, were prepared for targeting lung cancer. Transmission electron microscopy images and transfection photographs, respectively, showed that magnetic nanoparticles and pshRNA were successfully encased in the albumin nanospheres. The release profiles in vitro indicated that nanospheres had an obvious effect of sustained release of pshRNA. The results of slide agglutination test and immunofluorescence analysis demonstrated that the immuno-nanospheres retained the immuno-reactivity of Cetuximab. The MAINs significantly increased adherence and uptake by GLC-82 lung cancer cells over-expressed epidermal growth factor receptor over a magnetic albumin nanospheres (MANs) control. The pshRNA-loaded MAINs formulation was more effective than equimolar doses of free Cetuximab, single magnetic targeting with pshRNA (pshRNA-loaded MANs) or single monoclonal antibody targeting with pshRNA (pshRNA-loaded AINs) in the treatment of GLC-82 lung cancer cells. Collectively, the study indicates that the novel pshRNA-loaded magnetic immuno-nanospheres represent a promising approach for magnetic and monoclonal antibody-dependent gene targeting in lung cancer therapy.

  • Tris(2-aminoethyl)amine-based α-Branched Fatty Acid Amides - Synthesis of Lipids and Comparative Study of Transfection Efficiency of their Lipid Formulations.
    Erdmann N, Wölk C, Schulze I, et al. Tris(2-aminoethyl)amine-based α-Branched Fatty Acid Amides - Synthesis of Lipids and Comparative Study of Transfection Efficiency of their Lipid Formulations. [JOURNAL ARTICLE]Eur J Pharm Biopharm 2015 Aug 28.AbstractPublisher Full TextThe synthesis of a new class of cationic lipids, tris(2-aminoethyl)amine-based α-branched fatty acid amides, is described resulting in a series of lipids with specific variations in the lipophilic as well as the hydrophilic part of the lipids. In-vitro structure/transfection relationships were established by application of complexes of these lipids with plasmid DNA (pDNA) to different cell lines. The α-branched fatty acid amide bearing two tetradecyl chains and two lysine molecules (T14diLys) in mixture with the co-lipid 1,2-di-[(9Z)-octadec-9-enoyl]-sn-glycero-3-phosphoethanolamine (DOPE) (1/2, n/n) exhibits effective pDNA transfer in three different cell lines, namely Hep-G2, A549, and COS-7. The presence of 10% serum during lipoplex incubation of the cells did not affect the transfection efficiency. Based on that, detailed investigations of the complexation of pDNA with the lipid formulation T14diLys/DOPE 1/2 (n/n) were carried out with respect to particle size and charge using dynamic light scattering (DLS), ζ-potential measurements and transmission electron microscopy (TEM). Additionally, the lipoplex uptake was investigated by confocal laser scanning microscopy (CLSM). Overall, lipoplexes prepared from T14diLys/DOPE 1/2 (n/n) offer large potential as lipid-based polynucleotide carriers and further justify advanced examinations.

  • CAR therapy: the CD19 paradigm.
    Sadelain M CAR therapy: the CD19 paradigm. [Journal Article]J Clin Invest 2015 Sep 1; 125(9):3392-400.AbstractPublisher Full TextTwenty-five years after its inception, the genetic engineering of T cells is now a therapeutic modality pursued at an increasing number of medical centers. This immunotherapeutic strategy is predicated on gene transfer technology to instruct T lymphocytes to recognize and reject tumor cells. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and - in the case of second-generation CARs - costimulation to augment T cell functionality and persistence. We demonstrated over a decade ago that human T cells engineered with a CD19-specific CAR eradicated B cell malignancies in mice. Several phase I clinical trials eventually yielded dramatic results in patients with leukemia or lymphoma, especially acute lymphoblastic leukemia (ALL). This review recounts the milestones of CD19 CAR therapy and summarizes lessons learned from the CD19 paradigm.

  • Immunity, inflammation, and cancer: an eternal fight between good and evil.
    Shalapour S, Karin M Immunity, inflammation, and cancer: an eternal fight between good and evil. [Journal Article]J Clin Invest 2015 Sep 1; 125(9):3347-55.AbstractPublisher Full TextCancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches.

  • Platelets promote cartilage repair and chondrocyte proliferation via ADP in a rodent model of osteoarthritis.
    Zhou Q, Xu C, Cheng X, et al. Platelets promote cartilage repair and chondrocyte proliferation via ADP in a rodent model of osteoarthritis. [JOURNAL ARTICLE]Platelets 2015 Sep 1.:1-11.AbstractPublisher Full TextOsteoarthritis (OA) is the most common age-related degenerative joint disease and platelet-rich plasma (PRP) has been shown to be beneficial in OA. Therefore, in this study, we aimed to investigate the effects of platelets on chondrocytes and the underlying mechanisms. Anabolic and catabolic activity and the proliferation rate of chondrocytes were evaluated after co-culture with platelets. Chondrocyte gene expression was measured by real-time PCR. Chondrocyte protein expression and phosphorylation were measured by western blot. Chondrocytes treated with or without platelets were transplanted into a rat model of OA induced by intra-articular injection of monosodium iodoacetate and the repair of articular cartilage was evaluated macroscopically and histologically. Platelets significantly promoted the proliferation of chondrocytes, while mildly influencing anabolic and catabolic activity. Chondrocytes co-cultured with platelets showed significantly increased production of bone morphogenetic protein 7 (BMP7). The autocrine/paracrine effect of BMP7 was responsible for the increased proliferation of chondrocytes, via the ERK/CDK1/cyclin B1 signaling pathway. Transplantation of platelet-treated chondrocytes showed better cartilage repair in the OA model. Platelet-derived ADP was identified as the major mediator to promote the production of BMP7 and the proliferation of chondrocytes, through the ADP receptor P2Y1. Finally, direct injection of α,β-methyleneadenosine-5'-diphosphate into OA joints also enhanced cartilage repair. This study has identified that platelet-derived ADP, but not ATP, is the key mediator for platelet-promoted chondrocyte proliferation and cartilage repair in osteoarthritis. This finding may provide a key explanation for the therapeutic effect of platelets in OA and help shaping a strategy to improve OA therapy.

  • Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation.
    Lozano T, Villanueva L, Durántez M, et al. Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation. [JOURNAL ARTICLE]J Immunol 2015 Aug 31.AbstractPublisher Full TextRegulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4(+) T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.