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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.


  • Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for Limb Girdle Muscular Dystrophy 2D.
    Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for Limb Girdle Muscular Dystrophy 2D. [Journal Article]Hum Mol Genet 2018 Jan 16.HMCarotti M, Marsolier J, Soardi M, et al. Limb Girdle Muscular Dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease, affecting striated muscle, due to mutation of SGCA, the gene coding for α-sarcoglycan. Nowadays more than 50 diffe...Limb Girdle Muscular Dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease, affecting striated muscle, due to mutation of SGCA, the gene coding for α-sarcoglycan. Nowadays more than 50 different SGCA missense mutations have been reported. They are supposed to impact folding and trafficking of α-sarcoglycan because the defective polypeptide, although potentially functional, is recognized and disposed of by the quality control of the cell. The secondary reduction of α-sarcoglycan partners, β-, γ- and δ-sarcoglycan, disrupts a key membrane complex that, associated to dystrophin, contributes to assure sarcolemma stability during muscle contraction. The complex deficiency is responsible for muscle wasting and the development of a severe form of dystrophy.Here, we show that the application of small molecules developed to rescue ΔF508-CFTR trafficking, and known as CFTR correctors, also improved the maturation of several α-sarcoglycan mutants that were consequently rescued at the plasma membrane. Remarkably, in myotubes from a patient with LGMD2D, treatment with CFTR correctors induced the proper re-localization of the whole sarcoglycan complex, with a consequent reduction of sarcolemma fragility. Although the mechanism of action of CFTR correctors on defective α-sarcoglycan needs further investigation, this is the first report showing a quantitative and functional recovery of the sarcoglycan-complex in human pathologic samples, upon small molecule treatment. It represents the proof of principle of a pharmacological strategy that acts on the sarcoglycan maturation process and we believe it has a great potential to develop as a cure for most of the patients with LGMD2D.

  • Personalized Medicine in CF: From Modulator Development to Therapy for Cystic Fibrosis Patients with Rare CFTR Mutations.
    Personalized Medicine in CF: From Modulator Development to Therapy for Cystic Fibrosis Patients with Rare CFTR Mutations. [Journal Article]Am J Physiol Lung Cell Mol Physiol 2017 Dec 14.AJHarutyunyan M, Huang Y, Mun KS, et al. Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting approximately 1 in 3500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regu...Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting approximately 1 in 3500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, over 2000 CFTR mutations have been identified and produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small-molecules, or modulators, that can restore CFTR function. In recent years, two modulators, Ivacaftor (Kalydeco®) and Lumacaftor/Ivacaftor (Orkambi®), have been FDA-approved to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators' efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients. This review provides an overview of recent advances in the development of CFTR modulators, including those approved for clinical use and ones in various stages of development. Moreover, we summarize several CF cases with rare CFTR mutations and highlight the significance of personalized medicine in finding effective therapeutic options for these patients.

  • Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice.
    Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice. [Journal Article]PLoS One 2018; 13(1):e0190981.PlosMerentie M, Rissanen R, Lottonen-Raikaslehto L, et al. Vascular endothelial growth factor-A (VEGF-A) is the master regulator of angiogenesis, vascular permeability and growth. However, its role in mature blood vessels is still not well understood. To bette...Vascular endothelial growth factor-A (VEGF-A) is the master regulator of angiogenesis, vascular permeability and growth. However, its role in mature blood vessels is still not well understood. To better understand the role of VEGF-A in the adult vasculature, we generated a VEGF-A knockdown mouse model carrying a doxycycline (dox)-regulatable short hairpin RNA (shRNA) transgene, which silences VEGF-A. The aim was to find the critical level of VEGF-A reduction for vascular well-being in vivo. In vitro, the dox-inducible lentiviral shRNA vector decreased VEGF-A expression efficiently and dose-dependently in mouse endothelial cells and cardiomyocytes. In the generated transgenic mice plasma VEGF-A levels decreased shortly after the dox treatment but returned back to normal after two weeks. VEGF-A expression decreased shortly after the dox treatment only in some tissues. Surprisingly, increasing the dox exposure time and dose led to elevated VEGF-A expression in some tissues of both wildtype and knockdown mice, suggesting that dox itself has an effect on VEGF-A expression. When the effect of dox on VEGF-A levels was further tested in naïve/non-transduced cells, the dox administration led to a decreased VEGF-A expression in endothelial cells but to an increased expression in cardiomyocytes. In conclusion, the VEGF-A knockdown was achieved in a dox-regulatable fashion with a VEGF-A shRNA vector in vitro, but not in the knockdown mouse model in vivo. Dox itself was found to regulate VEGF-A expression explaining the unexpected results in mice. The effect of dox on VEGF-A levels might at least partly explain its previously reported beneficial effects on myocardial and brain ischemia. Also, this effect on VEGF-A should be taken into account in all studies using dox-regulated vectors.

  • Fibroblast growth factor receptor 1 amplification in laryngeal squamous cell carcinoma.
    Fibroblast growth factor receptor 1 amplification in laryngeal squamous cell carcinoma. [Journal Article]PLoS One 2018; 13(1):e0186185.PlosMonico J, Miller B, Rezeanu L, et al. Fibroblast growth factor receptor 1 (FGFR1) has been noted to be amplified in a variety of squamous cell carcinomas (SCCa) of the head, neck, and lung and increased copy number (CN) is a predictor of p...Fibroblast growth factor receptor 1 (FGFR1) has been noted to be amplified in a variety of squamous cell carcinomas (SCCa) of the head, neck, and lung and increased copy number (CN) is a predictor of poor outcomes. FGFR1 is a therapeutic target for lung SCCa and inhibition therapy is currently in clinical trials. Absolute quantification of FGFR1 from formalin fixed paraffin embedded (FFPE) tissue of laryngeal SCCa was examined in this retrospective study. A droplet digital polymerase chain reaction (ddPCR) was used for absolute quantitation of the FGFR1 gene CN. Of the 74 samples analyzed, FGFR1 CN analysis revealed 54% of samples had CN greater than 2 copies/cell (1.8-2.2 copies/cell), and 38% had CN values greater than 3. The mean and standard deviation FGFR1 CN was 4.17 ± 1.46 CN for African American patients (n = 41) and 3.78 ±1.85 CN for Caucasian patients (n = 31). Further, 60.9% of specimens from African Americans demonstrated increased FGFR1 CN compared to 48.4% of Caucasians. Two SCCA samples from Native American demonstrated increased FGFR1 CN (4.19 and 3.01 CN). The level of FGFR1 amplification did not correlate with tumor stage, lymph node staging, or metastasis. In this population, the proportion of patient samples with an FGFR1 amplification was three times higher than in reported for SCCA of the head and neck. Further, increased FGFR1 CN was observed in two racial groups not previously reported: African Americans and Native Americans. However, FGFR1 amplification is not prognostic in laryngeal squamous cell carcinomas.

  • mTOR Cross-Talk in Cancer and Potential for Combination Therapy.
    mTOR Cross-Talk in Cancer and Potential for Combination Therapy. [Journal Article, Review]Cancers (Basel) 2018 Jan 19; 10(1)CConciatori F, Ciuffreda L, Bazzichetto C, et al. The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pat...The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.

  • The role of patient registries for rare genetic lipid disorders.
    The role of patient registries for rare genetic lipid disorders. [Journal Article]Curr Opin Lipidol 2018 Jan 17.CONg DM, Hooper AJ, Bellgard MI, et al. There are currently few disease-specific rare lipid disorder patient registries. The very nature of rare genetic lipid disorders would suggest that larger national or international registries are neces...We review the role, utility and current status of patient registries for rare genetic lipid disorders.The creation and maintenance of rare genetic lipid disorder patient registries is critical for disease monitoring, improving clinical best practice, facilitating research and enabling the development of novel therapeutics. An open-source disease registry platform, termed the Rare Disease Registry Framework, has been developed, optimized and deployed for homozygous familial hypercholesterolemia. A global disease-specific registry for lipoprotein lipase deficiency (LPLD), GENetherapy In the mAnagement of Lipoprotein Lipase deficiency, has been established with the aim of enrolling 20-40% of LPLD patients worldwide and will study the natural history of LPLD as well as therapeutic response to the gene therapy alipogene tiparvovec. Similarly, a registry for lysosomal acid lipase deficiency patients in Europe and the United States is studying the clinical outcomes of the enzyme-replacement therapy sebelipase alfa.There are currently few disease-specific rare lipid disorder patient registries. The very nature of rare genetic lipid disorders would suggest that larger national or international registries are necessary to capture clinical data on a sufficient number of patients to provide insight into the prevalence and natural history of these conditions. Furthermore, these registries can help to identify and address deficiencies in current diagnostic and management practices, and facilitate clinical trials of new therapies.

  • Duchenne Muscular Dystrophy (DMD): An updated review of common available therapies.
    Duchenne Muscular Dystrophy (DMD): An updated review of common available therapies. [Journal Article]Int J Neurosci 2018 Jan 19.:1-24.IJSalmaninejad A, Valilou SF, Bayat H, et al. Duchenne muscular dystrophy (DMD) is a lethal progressive pediatric muscle disorder and genetically inherited as an X-linked disease that caused by mutations in the dystrophin gene. DMD leads to progre...Duchenne muscular dystrophy (DMD) is a lethal progressive pediatric muscle disorder and genetically inherited as an X-linked disease that caused by mutations in the dystrophin gene. DMD leads to progressive muscle weakness, degeneration, and wasting; finally, follows with the premature demise in affected individual's due to respiratory and/or cardiac failure typically by age of 30. For decades, scientists tried massively to find an effective therapy method, but there is no absolute cure currently for patients with DMD, nevertheless, recent advanced progressions on the treatment of DMD will be hopeful in the future. Several promising gene therapies are currently under investigation. These include gene replacement, exon skipping, suppression of stop codons. More recently, a promising gene editing tool referred to as CRISPR/Cas9 offers exciting perspectives for restoring dystrophin expression in patients with DMD. This review intents to briefly describe these methods and comment on their advances. Since DMD is a genetic disorder, it should be treated by replacing the deficient DMD copy with a functional one. However, there are different types of mutations in this gene, so such therapeutic approaches are highly mutation specific and thus are personalized. Therefore, DMD has arisen as a model of genetic disorder for understanding and overcoming of the challenges of developing personalized genetic medicines, consequently, the lessons learned from these approaches will be applicable to many other disorders. This review provides an update on the recent gene therapies for DMD that aim to compensate for dystrophin deficiency and the related clinical trials.

  • Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma.
    Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma. [Journal Article]Clin Exp Allergy 2018 Jan 19.CELooi K, Buckley AG, Rigby PJ, et al. This study demonstrates novel intrinsic differences in TJ gene and protein expression between AEC of children with and without asthma. Furthermore, it correlates directly the relationship between HRV i...Bronchial epithelial tight junctions (TJ) have been extensively assessed in healthy airway epithelium. However, no studies have yet assessed the effect of human rhinovirus (HRV) infection on the expression and resultant barrier function in epithelial tight junctions (TJ) in childhood asthma.To investigate the impact of HRV infection on airway epithelial TJ expression and barrier function in airway epithelial cells (AEC) of children with and without asthma. Furthermore, to test the hypothesis that barrier integrity and function is compromised to a greater extent by HRV in AECs from asthmatic children.Primary AEC were obtained from children with and without asthma, differentiated into Air Liquid Interface (ALI) cultures and infected with rhinovirus. Expression of claudin-1, occludin and zonula occluden-1 (ZO-1) was assessed via qPCR, immunocytochemistry (ICC), in-cell western (ICW) and confocal microscopy. Barrier function was assessed by transepithelial electrical resistance (TER; RT ) and permeability to fluorescent dextran.Basal TJ gene expression of claudin-1 and occludin was significantly upregulated in asthmatic children compared to non-asthmatics, however no difference was seen with ZO-1. Interestingly, claudin-1, occludin and ZO-1 protein expression was significantly reduced in AEC of asthmatic children compared to non-asthmatic controls suggesting possible post transcriptional inherent differences. HRV infection resulted in a transient dissociation of TJ and airway barrier integrity in non-asthmatic children. Although similar dissociation of TJ was observed in asthmatic children, a significant and sustained reduction of TJ expression concurrent with both a significant decrease in TER and an increase in permeability in asthmatic children was observed.This study demonstrates novel intrinsic differences in TJ gene and protein expression between AEC of children with and without asthma. Furthermore, it correlates directly the relationship between HRV infection and the resultant dissociation of epithelial TJ that causes a continued altered barrier function in children with asthma. This article is protected by copyright. All rights reserved.

  • TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence.
    TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence. [Journal Article]J Leukoc Biol 2018 Jan 19.JLSpear TT, Foley KC, Garrett-Mayer E, et al. T cell receptor (TCR) gene-modified T cells are a promising immunotherapy but require refinement to improve clinical responses and limit off-target toxicities. A variety of TCR and gene-delivery vector...T cell receptor (TCR) gene-modified T cells are a promising immunotherapy but require refinement to improve clinical responses and limit off-target toxicities. A variety of TCR and gene-delivery vector modifications have been developed to enhance introduced TCR expression and limit introduced/endogenous TCR chain mispairing, improving target antigen recognition and minimizing mispairing-induced cross-reactivity. Using our well-characterized HCV1406 TCR, we previously compared the impact of various chain pairing enhancing modifications on TCR expression and cognate antigen recognition. HCV1406 TCR is also natively cross-reactive against naturally occurring altered peptide ligands (APLs), which was shown to be dependent on high TCR surface density. In this report, we observed in a Jurkat model that absent TCR chain pairing competition alleviated CD8-dependent APL recognition and induced novel cross-reactivity of HCV1406 TCR. We then compared chain pairing enhancing modifications' effects on TCR cross-reactivity in Jurkat and T cells, showing C-terminal leucine zippers and constant region murinization alleviated CD8 dependence and induced novel APL recognition. While modifications enhancing TCR chain pairing intend to avoid cross-reactivity by limiting mispairing with the endogenous TCR, these data suggest they may also enhance natural cross-reactivity and reduce dependence on CD8. These observations have significant implications on the design/implementation of TCR gene-modified T cells.

  • CCAT1 stimulation of the symmetric division of NSCLC stem cells through activation of the Wnt signalling cascade.
    CCAT1 stimulation of the symmetric division of NSCLC stem cells through activation of the Wnt signalling cascade. [Journal Article]Gene Ther 2018 Jan 19.GTXu C, Xiao G, Zhang B, et al. Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells (CSCs) ...Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells (CSCs) leading to therapeutic resistance and adverse prognosis have not been well studied. CSCs frequently undergo symmetric division, which facilitates expansion of the stem cell pool, contributing to long-term relapse and therapy failure. CCAT1 could act as a miRNA sponge to influence downstream genes; however, its roles in NSCLC stem cell are unclear. We first identified activation of Wnt signalling in NSCLC. Analysis of the clinical data from a public database showed a significant decrease of the Wnt signalling repressor Let-7c. Using biological and informatics analyses, we hypothesized that CCAT1 stimulated the main factors of the Wnt signalling pathway, of which the three most deregulated genes were further confirmed by western blotting. Axitinib, a Wnt signalling inhibitor, effectively stimulated asymmetric division, similar to Let-7c. CCAT1 inhibition decreased the ratio of symmetric division of stem cells, and both Let-7c and Axitinib significantly abolished CCAT1 induction of symmetric division by inhibiting Wnt signalling. Restoration of Let-7c blocked the CCAT1 effects, forming the CCAT1/Let-7c/Wnt regulatory axis to control the division of lung cancer stem cells. Stimulation of stem cells to divide asymmetrically by delivering Let-7c or suppressive Axitinib could represent prospective strategies for curing lung cancer patients.Gene Therapy accepted article preview online, 19 January 2018. doi:10.1038/gt.2017.98.

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