Current Issue : October - December Volume : 2017 Issue Number : 4 Articles : 6 Articles
Aims We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DDNDC gene therapy in patients\nwith refractory angina.\nMethods and\nresults\nThirty patients were randomized to AdVEGF-DDNDC (AdVEGF-D) or placebo (control) groups. Electromechanical\nNOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was\ntargeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were\nmeasured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-\nmonths follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated\narea in the AdVEGF-D group compared with baseline (1.00 �± 0.36) at 3 months (1.31 �± 0.46, P = 0.045) and\n12 months (1.44 �± 0.48, P = 0.009) whereas MPR in the reference area tended to decrease (2.05 �± 0.69, 1.76 �± 0.62,\nand 1.87 �± 0.69; baseline, 3 and 12 months, respectively, P = 0.551). Myocardial perfusion reserve in the control\ngroup showed no significant change from baseline to 3 and 12 months (1.26 �± 0.37, 1.57 �± 0.55, and 1.48 �± 0.48; respectively,\nP = 0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased\nin 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline\nshowed the best response to therapy (MPR 0.94 �± 0.32 and 1.76 �± 0.41 baseline and 12 months, respectively,\nP = 0.023).\nConclusion AdVEGF-DDNDC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the\ntreated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that\nmay have the greatest benefit with this therapy....
Background and aims: Malignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint\nblockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be\nsevere. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate\nimmune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy\n(AdCD40L).\nMethods: Peripheral blood mononuclear cells and plasma were collected from malignant melanoma patients\n(n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose\ncyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array\nproteomics.\nResults: All patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors\nTNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6\ncorrelated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs),\nIL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival.\nConclusions: AdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged\nsurvival. Further studies using CD40 stimulation in malignant melanoma are warranted....
In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the\nCRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of\ninterest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for\ncombining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs.\nDMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which\nplays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be\ncapable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse\nmodels. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and\ndiscuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD\ncloser to the clinic....
Background: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical\nstudies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also\nidentified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T\nlymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other\nstrategies to reduce capsid antigen presentation are desirable.\nMethods: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B\nby hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated\nthrough molecular evolution.\nResults: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation\nFIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however,\nexpression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC\ncapsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog.\nConclusions: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in\nhepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict\nefficacy in other species and thus is of limited translational utility....
Clinical application of lentiviral vector (LV)-based hematopoietic\nstem and progenitor cells (HSPC) gene therapy is rapidly becoming\na reality. Nevertheless, LV-mediated signaling and its potential\nfunctional consequences on HSPC biology remain poorly understood.\nWe unravel here a remarkably limited impact of LV on the\nHSPC transcriptional landscape. LV escaped innate immune sensing\nthat instead led to robust IFN responses upon transduction with a\ngamma-retroviral vector. However, reverse-transcribed LV DNA did\ntrigger p53 signaling, activated also by non-integrating Adenoassociated\nvector, ultimately leading to lower cell recovery ex vivo\nand engraftment in vivo. These effects were more pronounced in\nthe short-term repopulating cells while long-term HSC frequencies\nremained unaffected. Blocking LV-induced signaling partially\nrescued both apoptosis and engraftment, highlighting a novel\nstrategy to further dampen the impact of ex vivo gene transfer on\nHSPC. Overall, our results shed light on viral vector sensing in HSPC\nand provide critical insight for the development of more stealth\ngene therapy strategies....
The transcription factor ICP4 from herpes simplex\nvirus has a central role in regulating the gene expression\ncascade which controls viral infection. Here\nwe present the crystal structure of the functionally\nessential ICP4 DNA binding domain in complex\nwith a segment from its own promoter, revealing a\nnovel homo-dimeric fold. We also studied the complex\nin solution by small angle X-Ray scattering, nuclear\nmagnetic resonance and surface-plasmon resonance\nwhich indicated that, in addition to the globular\ndomain, a flanking intrinsically disordered region\nalso recognizes DNA. Together the data provides a\nrationale for the bi-partite nature of the ICP4 DNA\nrecognition consensus sequence as the globular and\ndisordered regions bind synergistically to adjacent\nDNA motifs. Therefore in common with its eukaryotic\nhost, the viral transcription factor ICP4 utilizes\ndisordered regions to enhance the affinity and tune\nthe specificity of DNA interactions in tandem with a\nglobular domain....
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