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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.


  • mT-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
    mT-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy. [Journal Article]PLoS Pathog 2017 Sep 20; 13(9):e1006629.PPThomas AS, Jones KL, Gandhi RT, et al. HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that rema...HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

  • Detection of Residual Donor Erythroid Progenitor Cells after Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies.
    Detection of Residual Donor Erythroid Progenitor Cells after Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies. [Journal Article]J Vis Exp 2017 Sep 06; (127)JVCrazzolara R, Kropshofer G, Steurer M, et al. The presence of incomplete chimerism is noted in a large proportion of patients following bone marrow transplant for thalassemia major or sickle cell disease. This observation has tremendous implicatio...The presence of incomplete chimerism is noted in a large proportion of patients following bone marrow transplant for thalassemia major or sickle cell disease. This observation has tremendous implications, as subsequent therapeutic immunomodulation strategies can improve clinical outcome. Conventionally, polymerase chain reaction-based analysis of short tandem repeats is used to identify chimerism in donor-derived blood cells. However, this method is restricted to nucleated cells and cannot distinguish between dissociated single-cell lineages. We applied the analysis of short tandem repeats to flow cytometric-sorted hematopoietic progenitor cells and compared this with the analysis of short tandem repeats obtained from selected burst-forming unit - erythroid colonies, both collected from the bone marrow. With this method we are able to demonstrate the different proliferation and differentiation of donor cells in the erythroid compartment. This technique is eligible to complete current monitoring of chimerism in the stem cell transplant setting and thus may be applied in future clinical studies, stem cell research and design of gene therapy trials.

  • Genetic addiction risk score (GARS) ™, a predictor of vulnerability to opioid dependence.
    Genetic addiction risk score (GARS) ™, a predictor of vulnerability to opioid dependence. [Journal Article]Front Biosci (Elite Ed) 2018 Jan 01.:175-196.FBBlum K, Chen ALC, Thanos PK, et al. The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individua...The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. This discussion authored by a group of concerned scientists and clinicians examines the Genetic Addiction Risk Score (GARS), the first test to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as Reward Deficiency Syndrome (RDS). Innovative strategies to combat epidemic opioid, iatrogenic prescription drug abuse and death, based on the role of dopaminergic tone in pain pathways, are proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance. They provide unique therapeutic targets that could assist in the treatment of pain, and identify risk for subsequent addiction. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Genetically identifying risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities to provide better resource allocation.

  • Selective HDL-Raising Human Apo A-I Gene Therapy Counteracts Cardiac Hypertrophy, Reduces Myocardial Fibrosis, and Improves Cardiac Function in Mice with Chronic Pressure Overload.
    Selective HDL-Raising Human Apo A-I Gene Therapy Counteracts Cardiac Hypertrophy, Reduces Myocardial Fibrosis, and Improves Cardiac Function in Mice with Chronic Pressure Overload. [Journal Article]Int J Mol Sci 2017 Sep 20; 18(9)IJAmin R, Muthuramu I, Aboumsallem JP, et al. Epidemiological studies support an independent inverse association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. The effect of selective HDL-raising adeno-assoc...Epidemiological studies support an independent inverse association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. The effect of selective HDL-raising adeno-associated viral serotype 8-human apolipoprotein (apo) A-I (AAV8-A-I) gene transfer on cardiac remodeling induced by transverse aortic constriction (TAC) was evaluated in C57BL/6 low-density lipoprotein receptor-deficient mice. Septal wall thickness and cardiomyocyte cross-sectional area were reduced by 16.5% (p < 0.001) and by 13.8% (p < 0.01), respectively, eight weeks after TAC in AAV8-A-I mice (n = 24) compared to control mice (n = 39). Myocardial capillary density was 1.11-fold (p < 0.05) higher and interstitial cardiac fibrosis was 45.3% (p < 0.001) lower in AAV8-A-I TAC mice than in control TAC mice. Lung weight and atrial weight were significantly increased in control TAC mice compared to control sham mice, but were not increased in AAV8-A-I TAC mice. The peak rate of isovolumetric contraction was 1.19-fold (p < 0.01) higher in AAV8-A-I TAC mice (n = 17) than in control TAC mice (n = 29). Diastolic function was also significantly enhanced in AAV8-A-I TAC mice compared to control TAC mice. Nitro-oxidative stress and apoptosis were significantly reduced in the myocardium of AAV8-A-I TAC mice compared to control TAC mice. In conclusion, selective HDL-raising human apo A-I gene transfer potently counteracts the development of pressure overload-induced cardiomyopathy.

  • Editorial: Gene Therapy for Fanconi Anemia Enters a New Clinical Era.
    Editorial: Gene Therapy for Fanconi Anemia Enters a New Clinical Era. [Editorial]Curr Gene Ther 2017; 16(5):296.CGVerhoeyen E 

  • The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency.
    The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency. [Journal Article]Postgrad Med 2017 Sep 20.PMLascano JE, Campos MA Improving primary care provider awareness and promoting regular reflex testing all COPD patients for AATD may significantly improve the care of COPD patients.Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder that can cause chronic obstructive pulmonary disease (COPD) and liver cirrhosis, two clinical conditions commonly seen by primary care physicians. AATD is estimated to affect 1/4000-1/5000 people in the United States and 1-2% of all COPD cases.PubMed was searched for relevant articles using AAT/AATD-related terms.Unfortunately, <10% of symptomatic individuals have been properly diagnosed primarily due to the underdiagnosis of COPD and the lack of awareness of AATD as a possible underlying cause. Because primary care providers are most likely to be the first to encounter symptomatic individuals, their role in the identification and early diagnosis of AATD patients is instrumental, particularly since therapy to slow lung disease progression is available. The diagnosis of AATD is laboratory-based rather than clinical. Testing for AATD should be part of the reflex testing that follows any COPD diagnosis or unexplained liver disease and can be performed by determining the AAT phenotype or genotype along with serum AAT levels. Both nonpharmacological and pharmacological approaches are recommended for treatment of lung disease, including smoking cessation, bronchodilators or supplemental oxygen as needed. Specific augmentation of AAT levels with regular purified AAT infusions has been found to slow lung function decline and emphysema progression in patients with moderate airflow obstruction and severely low serum AAT levels.Improving primary care provider awareness and promoting regular reflex testing all COPD patients for AATD may significantly improve the care of COPD patients.

  • New Drugs in the Pipeline for the Treatment of HIV: a Review.
    New Drugs in the Pipeline for the Treatment of HIV: a Review. [Journal Article, Review]Curr Infect Dis Rep 2017 Sep 19; 19(11):42.CIGravatt LAH, Leibrand CR, Patel S, et al. The purpose of this paper is to review therapies with new mechanisms of action for the treatment of HIV that are at least in phase 2 clinical trials.The purpose of this paper is to review therapies with new mechanisms of action for the treatment of HIV that are at least in phase 2 clinical trials.There are several new mechanisms of action being represented within clinical development, including histone deacetylase (HDAC) inhibitors, gene therapies, broadly neutralizing anti-HIV antibodies, immune modulation, and drugs with new mechanisms to block HIV entry. The new therapies are being developed for both as add-on therapy to existing combination antiretroviral therapy and as agents to be used during treatment interruption. The current drugs in development have had varying degrees of success in the early trials. Each of these new drugs may potentially fill a void in current antiretroviral therapy (ART) therapies, which will ultimately lead to improved outcomes in HIV-infected individuals.

  • Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model.
    Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model. [Journal Article]J Neurooncol 2017 Sep 19.JNHaryu S, Saito R, Jia W, et al. Expression of CD44 in glioma cells was previously correlated with tumor grade and is considered a stem cell marker. CD44 stabilizes the cystine-glutamate transporter (xCT) and inhibits apoptosis in can...Expression of CD44 in glioma cells was previously correlated with tumor grade and is considered a stem cell marker. CD44 stabilizes the cystine-glutamate transporter (xCT) and inhibits apoptosis in cancer stem cells (CSCs). Recently it was found that Sulfasalazine (SSZ), an anti-inflammatory drug, acts as an inhibitor of xCT and therefore has potential as a targeted therapy for CSCs. In this study, we tested an efficacy of SSZ against glioma stem cell model developed in rats. As poor penetration of blood-brain barrier resulted in insufficient efficacy of systemic SSZ treatment, SSZ was delivered locally with convection-enhanced delivery (CED). In vitro, expression of CD44 in glioma cells and efficacy of SSZ against glioma cells and glioma stem cells were confirmed. SSZ demonstrated anti-proliferative activity in a dose dependent manner against these cells. This activity was partially reversible with the addition of antioxidant, N-acetyl-L-cysteine, to the medium. In vivo, CED successfully delivered SSZ into the rat brain parenchyma. When delivered at 5 mM concentration, which was the highest possible concentration when SSZ was dissolved in water, CED of SSZ resulted in almost no tissue damage. Against highly malignant bRiTs-G3 brain tumor xenografted rat model; the glioma stem cell model, CED of SSZ at 5 mM concentration induced apoptosis and prolonged survival. Consequently, CED of SSZ induced glioma stem cell death without evidence of tissue damage to normal brain parenchyma. This strategy may be a promising targeted treatment against glioma stem cells.

  • An Insight into Phage Diversity at Environmental Habitats using Comparative Metagenomics Approach.
    An Insight into Phage Diversity at Environmental Habitats using Comparative Metagenomics Approach. [Journal Article]Curr Microbiol 2017 Sep 19.CMParmar K, Dafale N, Pal R, et al. Bacteriophages play significant role in driving microbial diversity; however, little is known about the diversity of phages in different ecosystems. A dynamic predator-prey mechanism called "kill the w...Bacteriophages play significant role in driving microbial diversity; however, little is known about the diversity of phages in different ecosystems. A dynamic predator-prey mechanism called "kill the winner" suggests the elimination of most active bacterial populations through phages. Thus, interaction between phage and host has an effect on the composition of microbial communities in ecosystems. In this study, secondary phage metagenome data from aquatic habitats: wastewater treatment plant (WWTP), fresh, marine, and hot water spring habitat were analyzed using MG-RAST and STAMP tools to explore the diversity of the viruses. Differential relative abundance of phage families-Siphoviridae (34%) and Myoviridae (26%) in WWTP, Myoviridae (30%) and Podoviridae (23%) in fresh water, and Myoviridae (41%) and Podoviridae (8%) in marine-was found to be a discriminating factor among four habitats while Rudiviridae (9%), Globuloviridae (8%), and Lipothrixviridae (1%) were exclusively observed in hot water spring. Subsequently, at genera level, Bpp-1-like virus, Chlorovirus, and T4-like virus were found abundant in WWTP, fresh, and marine habitat, respectively. PCA analysis revealed completely disparate composition of phage in hot water spring from other three ecosystems. Similar analysis of relative abundance of functional features corroborated observations from taxa analysis. Functional features corresponding to phage packaging machinery, replication, integration and excision, and gene transfer discriminated among four habitats. The comparative metagenomics approach exhibited genetically distinct phage communities among four habitats. Results revealed that selective distribution of phage communities would help in understanding the role of phages in food chains, nutrient cycling, and microbial ecology. Study of specific phages would also help in controlling environmental pathogens including MDR bacterial populations using phage therapy approach by selective mining and isolation of phages against specific pathogens persisting in a given environment.

  • Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells.
    Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells. [Journal Article]Front Pediatr 2017.:194.FPIwatani S, Harahap NIF, Nurputra DK, et al. UC-MSCs isolated from 17 fetus/infant of 19-40 weeks of gestation are expressed functional SMN mRNA and protein. SMN mRNA and protein expression in UC-MSCs is increased with gestational age during peri...Spinal muscular atrophy (SMA) is the most common genetic neurological disease leading to infant death. It is caused by loss of survival motor neuron (SMN) 1 gene and subsequent reduction of SMN protein in motor neurons. Because SMN is ubiquitously expressed and functionally linked to general RNA metabolism pathway, fibroblasts (FBs) are most widely used for the assessment of SMN expression in SMA patients but usually isolated from skin biopsy samples after the onset of overt symptoms. Although recent translational studies of SMN-targeted therapies have revealed the very limited time window for effective SMA therapies during perinatal period, the exact time point when SMN shortage became evident is unknown in human samples. In this study, we analyzed SMN mRNA and protein expression during perinatal period by using umbilical cord-derived mesenchymal stem cells (UC-MSCs) obtained from preterm and term infants.UC-MSCs were isolated from 16 control infants delivered at 22-40 weeks of gestation and SMA fetus aborted at 19 weeks of gestation (UC-MSC-Control and UC-MSC-SMA). FBs were isolated from control volunteer and SMA patient (FB-Control and FB-SMA). SMN mRNA and protein expression in UC-MSCs and FBs was determined by RT-qPCR and Western blot.UC-MSC-Control and UC-MSC-SMA expressed the comparable level of MSC markers on their cell surface and were able to differentiate into adipocytes, osteocytes, and chondrocytes. At steady state, SMN mRNA and protein expression was decreased in UC-MSC-SMA compared to UC-MSC-Control, as observed in FB-SMA and FB-Control. In response to histone deacetylase inhibitor valproic acid, SMN mRNA and protein expression in UC-MSC-SMA and FB-SMA was increased. During perinatal development from 22 to 40 weeks of gestation, SMN mRNA and protein expression in UC-MSC-Control was positively correlated with gestational age.UC-MSCs isolated from 17 fetus/infant of 19-40 weeks of gestation are expressed functional SMN mRNA and protein. SMN mRNA and protein expression in UC-MSCs is increased with gestational age during perinatal development.

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