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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.


  • TLR3 or TLR4 Activation Enhances MSC-Mediated Treg Induction via Notch Signaling.
    Rashedi I, Gomez-Aristizábal A, Wang XH, et al. TLR3 or TLR4 Activation Enhances MSC-Mediated Treg Induction via Notch Signaling. [JOURNAL ARTICLE]Stem Cells 2016 Aug 29.Mesenchymal stromal cells (MSCs) are the subject of numerous clinical trials, largely due to their immunomodulatory and tissue regenerative properties. Toll-like receptors (TLRs), especially TLR3 and TLR4, are highly expressed on MSCs and their activation can significantly modulate the immunosuppressive and anti-inflammatory functions of MSCs. While MSCs can recruit and promote the generation of regulatory T cells (Tregs), the effect of TLR activation on MSC-mediated Treg induction is unknown. In this study, we investigated the effect of ligand-mediated activation of TLR3 and TLR4 on Treg induction by human MSCs. We found that generation of Tregs in human CD4(+) lymphocyte and MSC cocultures was enhanced by either TLR3 or TLR4 activation of MSCs and that the increase was abolished by TLR3 and TLR4 gene-silencing. Augmented Treg induction by TLR-activated MSCs was cell contact-dependent and associated with increased gene expression of the Notch ligand, delta-like 1 (DL1). Moreover, inhibition of Notch signaling abrogated the augmented Treg levels in the MSC co-cultures. Our data show that TLR3 or TLR4 activation of MSCs increases Treg induction via the Notch pathway and suggest new means to enhance the potency of MSCs for treating disorders with an underlying immune dysfunction, including steroid resistant acute graft-versus-host disease. This article is protected by copyright. All rights reserved.

  • [Non-alcoholic fatty liver disease (NAFLD).]
    Bugianesi E, Marietti M [Non-alcoholic fatty liver disease (NAFLD).] [JOURNAL ARTICLE, ENGLISH ABSTRACT]Recenti Prog Med 2016 Jul; 107(7):360-368.AbstractPublisher Full TextNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and in the pediatric population of the western world; in a substantial proportion of subjects it takes on the characteristics of non-alcoholic steatohepatitis (NASH). The clinical significance of NAFLD is motivated by epidemiological data and its impact on liver-related morbidity and mortality on one hand and on the cardiovascular one on the other. The presence and extent of fibrosis on liver biopsy is the most relevant feature in predicting liver mortality, but the concept that the "simple steatosis" is benign has been recently questioned, especially in the presence of type 2 diabetes. Because the diagnosis of NASH is made by liver biopsy, the efforts of the scientific community are currently oriented to the search of non-invasive biomarkers of liver injury applicable on a large scale and of genetic polymorphisms associated to NASH in order to properly address the screening programs, follow-up and therapeutic attempts. Next to the therapy directed to the treatment of concomitant metabolic disorders, new drugs are being evaluated in clinical trials having as target the histologic resolution of NASH and regression of fibrosis.

  • Adeno-Associated Viral Vector Delivery to the Enteric Nervous System: A Review.
    Gombash SE Adeno-Associated Viral Vector Delivery to the Enteric Nervous System: A Review. [JOURNAL ARTICLE]Postdoc J 2015 Aug; 3(8):1-12.Gene therapy to the gastrointestinal tract has remarkable potential for treating gastrointestinal disorders that currently lack effective treatments. Adeno-associated viral vectors (AAVs) have been extensively applied to the central nervous system, and have repeatedly demonstrated safety and efficacy in animal models. The enteric nervous system (ENS) represents a vast collection of neurons and glial cells that may also be subject to treatment by AAV, however little work has been conducted on AAV delivery to the ENS. Challenges for gastrointestinal gene therapy include identifying gene targets, optimizing gene delivery, and target cell selection. Researchers are now beginning to tackle the later of the two challenges with AAV, and the same AAV technology can be used to identify novel gene targets in the future. Continued efforts to understand AAV delivery and improve vector design are essential for therapeutic development. This review summarizes the current knowledge about AAV delivery to the ENS.

  • Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer.
    Shroff S, Zhang J, Huang K Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer. [Journal Article]AMIA Jt Summits Transl Sci Proc 2016.:32-41.Responsiveness to drugs is an important concern in designing personalized treatment for cancer patients. Currently genetic markers are often used to guide targeted therapy. However, deeper understanding of the molecular basis for drug responses and discovery of new predictive biomarkers for drug sensitivity are much needed. In this paper, we present a workflow for identifying condition-specific gene co-expression networks associated with responses to the tyrosine kinase inhibitor, Erlotinib, in lung adenocarcinoma cell lines using data from the Cancer Cell Line Encyclopedia by combining network mining and statistical analysis. Particularly, we have identified multiple gene modules specifically co-expressed in the drug responsive cell lines but not in the unresponsive group. Interestingly, most of these modules are enriched on specific cytobands, suggesting potential copy number variation events on these loci. Our results therefore imply that there are multiple genetic loci with copy number variations associated with the Erlotinib responses. The existence of CNVs in these loci is also confirmed in lung cancer tissue samples using the TCGA data. Since these structural variations are inferred from functional genomics data, these CNVs are functional variations. These results suggest the condition specific gene co- expression network mining approach is an effective approach in predicting candidate biomarkers for drug responses.

  • A novel three-way rearrangement involving ETV6 (12p13) and ABL1 (9q34) with an unknown partner on 3p25 resulting in a possible ETV6-ABL1 fusion in a patient with acute myeloid leukemia: a case report and a review of the literature.
    Tirado CA, Siangchin K, Shabsovich DS, et al. A novel three-way rearrangement involving ETV6 (12p13) and ABL1 (9q34) with an unknown partner on 3p25 resulting in a possible ETV6-ABL1 fusion in a patient with acute myeloid leukemia: a case report and a review of the literature. [Journal Article]Biomark Res 2016; 4(1):16.Acute myeloid leukemia (AML) is commonly characterized by several chromosomal abnormalities resulting in the formation of chimeric genes that play various roles in leukemogenesis. Translocations resulting in the ETV6-ABL1 fusion gene are rare in AML and other hematologic malignancies with only thirty-two previously reported cases in the literature, five of which were AML.Herein, we report the case of a 73-year-old male with acute myeloid leukemia arising from MDS, negative for PDGFRA and PDGFRB, positive for bone marrow eosinophilia, rash, and marked fluid retention, which improved dramatically with imatinib therapy. Conventional cytogenetics revealed a t(3;9)(p25;q34), t(5;18)(q13;p11.2), and additional material of unknown origin at 12p11.2 in 2 out of 10 metaphases analyzed. Interphase FISH studies showed evidence of ETV6 (12p13) and ABL1 (9q34) rearrangements in 41.3 % and 5.7 % of the cells respectively. FISH studies on previously G-banded metaphases showed colocalization of ABL1 and ETV6 signals to the short arm of chromosome 3 at 3p25 suggesting a possible ETV6-ABL1 fusion. Subtelomeric metaphase FISH studies also showed the presence of a subtelomere 3p signal on the long arm of the derivative 9, and no subtelomere 3p signal on the derivative chromosome 12.These findings suggest a complex rearrangement involving an insertion of ETV6 into 3p25 followed by a reciprocal translocation involving 3p25 and 9q34, resulting in a possible ETV6-ABL1 fusion. This case highlights the importance of FISH to characterize complex rearrangements in myeloid malignancies, particularly those resulting in clinically significant chimeric genes.

  • Risk of discontinuation of Advanced Therapy Medicinal Products clinical trials.
    Hanna E, Rémuzat C, Auquier P, et al. Risk of discontinuation of Advanced Therapy Medicinal Products clinical trials. [Journal Article]J Mark Access Health Policy 2016.Advanced therapy medicinal products (ATMPs) constitute a class of innovative products that encompasses gene therapy, somatic cell therapy, and tissue-engineered products (TEP). There is an increased investment of commercial and non-commercial sponsors in this field and a growing number of ATMPs randomized clinical trials (RCT) and patients enrolled in such trials. RCT generate data to prove the efficacy of a new therapy, but the discontinuation of RCTs wastes scarce resources. Our objective is to identify the number and characteristics of discontinued ATMPs trials in order to evaluate the rate of discontinuation.We searched for ATMPs trials conducted between 1999 to June 2015 using three databases, which are Clinicaltrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the EU Drug Regulating Authorities Clinical Trials (EudraCT). We selected the ATMPs trials after elimination of the duplicates. We identified the disease areas and the sponsors as commercial or non-commercial organizations. We classified ATMPs by type and trial status, that is, ongoing, completed, terminated, discontinued, and prematurely ended. Then, we calculated the rate of discontinuation.Between 1999 and June 2015, 143 withdrawn, terminated, or prematurely ended ATMPs clinical trials were identified. Between 1999 and June 2013, 474 ongoing and completed clinical trials were identified. Therefore, the rate of discontinuation of ATMPs trials is 23.18%, similar to that for non-ATMPs drugs in development. The probability of discontinuation is, respectively, 27.35, 16.28, and 16.34% for cell therapies, gene therapies, and TEP. The highest discontinuation rate is for oncology (43%), followed by cardiology (19.2%). It is almost the same for commercial and non-commercial sponsors; therefore, the discontinuation reason may not be financially driven.No failure risk rate per development phase is available for ATMPs. The discontinuation rate may prove helpful when assessing the expected net present value to support portfolio arbitration and may be considered by patients and potential investigators in their decisions to participate in ATMP trials. These results carry limitation because the rationale for discontinuation is unknown. Further research about the reasons of discontinuation and the risk of negative results is needed to inform stakeholders.

  • Melatonin Treatment Improves Mesenchymal Stem Cells Therapy by Preserving Stemness during Long-term In Vitro Expansion.
    Shuai Y, Liao L, Su X, et al. Melatonin Treatment Improves Mesenchymal Stem Cells Therapy by Preserving Stemness during Long-term In Vitro Expansion. [Journal Article]Theranostics 2016; 6(11):1899-917.Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSCs therapy. Here, we report a melatonin-based strategy to improve cell therapy of in vitro cultured MSCs. Among four small molecules with anti-aging and stem cell-protection properties (rapamycin, resveratrol, quercetin and melatonin), colony forming, proliferation, and osteogenic differentiation assay showed that melatonin was the most efficient to preserve self-renewal and differentiation properties of rat bone marrow MSCs (BMMSCs) after long-term passaging. Functional assays confirmed melatonin treatment did not affect the colony forming, proliferation and osteogenic differentiation of BMMSCs cultured for 1 or 4 passages, but largely prevented the decline of self-renew and differentiation capacity of BMMSCs cultured for 15 passages in vitro. Furthermore, heterotopic osteogenesis assay, critical size calvarial defects repair assay, osteoporosis treatment and experimental colitis therapy assay strongly certified that melatonin preserved the therapeutic effect of long-term passaged BMMSCs on bone regeneration and immunotherapy in vivo. Mechanistically, melatonin functioned by activating antioxidant defense system, inhibiting the pathway of cell senescence, and preserving the expression of gene governing the stemness. Taken together, our findings showed that melatonin treatment efficiently prevented the dysfunction and therapeutic failure of BMMSCs after long-term passaging, providing a practical strategy to improve the application of BMMSCs in tissue engineering and cytotherapy.

  • Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures.
    Kurian SM, Novais M, Whisenant T, et al. Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures. [Journal Article]Theranostics 2016; 6(11):1792-809.AbstractPublisher Full TextEarly diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy.Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment.This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.

  • Gene, Stem Cell, and Alternative Therapies for SCA 1.
    Wagner JL, O'Connor DM, Donsante A, et al. Gene, Stem Cell, and Alternative Therapies for SCA 1. [Journal Article, Review]Front Mol Neurosci 2016.:67.Spinocerebellar ataxia 1 is an autosomal dominant disease characterized by neurodegeneration and motor dysfunction. In disease pathogenesis, polyglutamine expansion within Ataxin-1, a gene involved in transcriptional repression, causes protein nuclear inclusions to form. Most notably, neuronal dysfunction presents in Purkinje cells. However, the effect of mutant Ataxin-1 is not entirely understood. Two mouse models are employed to represent spinocerebellar ataxia 1, a B05 transgenic model that specifically expresses mutant Ataxin-1 in Purkinje cells, and a Sca1 154Q/2Q model that inserts the polyglutamine expansion into the mouse Ataxin-1 locus so that the mutant Ataxin-1 is expressed in all cells that express Ataxin-1. This review aims to summarize and evaluate the wide variety of therapies proposed for spinocerebellar ataxia 1, specifically gene and stem cell therapies.

  • Role of tyrosine-kinase inhibitors in myeloproliferative neoplasms: comparative lessons learned.
    Pinilla-Ibarz J, Sweet KL, Corrales-Yepez GM, et al. Role of tyrosine-kinase inhibitors in myeloproliferative neoplasms: comparative lessons learned. [Journal Article, Review]Onco Targets Ther 2016.:4937-57.An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR-ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR-ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR-ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib - the first therapy approved for MF worldwide - improved disease-related splenomegaly and symptoms independent of JAK2 (V617F) mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN - polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs. Here, we discuss the role of tyrosine-kinase inhibitors in the current MPN-treatment landscape.

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