Gene Transfer to the Heart: Emerging Strategies for the Selection of Vectors, Delivery Techniques, and Therapeutic Targets

2013 ◽  
pp. 169-206
Author(s):  
Michael G. Katz ◽  
Anthony S. Fargnoli ◽  
Louella A. Pritchette ◽  
Charles R. Bridges
Keyword(s):  
Gene Transfer ◽  
Therapeutic Targets ◽  
Selection Of ◽  
Delivery Techniques

scholarly journals Selection of Donor Nuclei in Somatic Cell-Mediated Gene Transfer Using a Co-Transfection Method

2007 ◽  
Vol 53 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Hairong MA ◽  
Zili LU ◽  
Yi SUN ◽  
Tao PENG ◽  
Zhiqiang SHUAI ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Somatic Cell ◽  
Transfection Method ◽  
Selection Of

Keeping up with the clinical advances: depression

CNS Spectrums ◽  
2019 ◽  
Vol 24 (S1) ◽  
pp. 25-37 ◽  
Author(s):  
Renee-Marie Ragguett ◽  
Jocelyn K. Tamura ◽  
Roger S. McIntyre
Keyword(s):  
Treatment Options ◽  
Therapeutic Targets ◽  
Rapid Response ◽  
Opioidergic System ◽  
Capital Costs ◽  
Preclinical Trials ◽  
Resistant Depression ◽  
Clinical Advances ◽  
Inflammatory System ◽  
Selection Of

Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.

Gene therapy for Cystic Fibrosis: Improved delivery techniques and conditioning with lysophosphatidylcholine enhance lentiviral gene transfer in mouse lung airways

2017 ◽  
Vol 43 (9-10) ◽  
pp. 426-433 ◽  
Author(s):  
Patricia Cmielewski ◽  
Nigel Farrow ◽  
Sharnna Devereux ◽  
David Parsons ◽  
Martin Donnelley
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Mouse Lung ◽  
Lung Airways ◽  
Delivery Techniques

Successful treatment of murine β-thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 506-513 ◽  
Author(s):  
Derek A. Persons ◽  
Esther R. Allay ◽  
Nobukuni Sawai ◽  
Phillip W. Hargrove ◽  
Thomas P. Brent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Drug Resistant ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Selection Of

AbstractSuccessful gene therapy of β-thalassemia will require replacement of the abnormal erythroid compartment with erythropoiesis derived from genetically corrected, autologous hematopoietic stem cells (HSCs). However, currently attainable gene transfer efficiencies into human HSCs are unlikely to yield sufficient numbers of corrected cells for a clinical benefit. Here, using a murine model of β-thalassemia, we demonstrate for the first time that selective enrichment in vivo of transplanted, drug-resistant HSCs can be used therapeutically and may therefore be a useful approach to overcome limiting gene transfer. We used an oncoretroviral vector to transfer a methylguanine methyltransferase (MGMT) drug-resistance gene into normal bone marrow cells. These cells were transplanted into β-thalassemic mice given nonmyeloablative pretransplantation conditioning with temozolomide (TMZ) and O6-benzylguanine (BG). A majority of mice receiving 2 additional courses of TMZ/BG demonstrated in vivo selection of the drug-resistant cells and amelioration of anemia, compared with untreated control animals. These results were extended using a novel γ-globin/MGMT dual gene lentiviral vector. Following drug treatment, normal mice that received transduced cells had an average 67-fold increase in γ-globin expressing red cells. These studies demonstrate that MGMT-based in vivo selection may be useful to increase genetically corrected cells to therapeutic levels in patients with β-thalassemia.

scholarly journals Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors

Gene Therapy ◽  
2011 ◽  
Vol 19 (8) ◽  
pp. 800-809 ◽  
Author(s):  
K Varadi ◽  
S Michelfelder ◽  
T Korff ◽  
M Hecker ◽  
M Trepel ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Gene Transfer ◽  
Peptide Libraries ◽  
Random Peptide ◽  
Random Peptide Libraries ◽  
Transfer Vectors ◽  
Selection Of

scholarly journals The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Ugo Testa ◽  
Elvira Pelosi
Keyword(s):  
Therapeutic Targets ◽  
Driver Mutations ◽  
Causative Role ◽  
Genetic Studies ◽  
Internal Tandem Duplication ◽  
Genetic Abnormalities ◽  
Myeloid Leukemias ◽  
The Impact ◽  
Selection Of ◽  
Acute Myeloid

The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients.

scholarly journals Ex vivo expansion and selection of human CD34+ peripheral blood progenitor cells after introduction of a mutated dihydrofolate reductase cDNA via retroviral gene transfer

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 566-574 ◽  
Author(s):  
M Flasshove ◽  
D Banerjee ◽  
S Mineishi ◽  
MX Li ◽  
JR Bertino ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Progenitor Cells ◽  
Dihydrofolate Reductase ◽  
Peripheral Blood ◽  
Liquid Culture ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Precursor Cells ◽  
Retroviral Gene Transfer ◽  
Selection Of

Abstract Retroviral gene transfer into human myeloid precursor cells allows introduction of marker genes as well as genes conferring resistance to chemotherapeutic drugs. We transduced a human mutant dihydrofolate reductase (DHFR) cDNA into CD34 antigen-positive peripheral blood cells from patients with breast or ovarian cancer obtained after treatment with chemotherapy and granulocyte colony-stimulating factor (G-CSF). This mutant DHFR has been shown to confer resistance to methotrexate (MTX) in murine bone marrow. We established a transduction protocol that permitted ex vivo expansion and selection of transduced early progenitor cells. The number of progenitor cells from transduced CD34- positive cells increased 50-fold after cytokine prestimulation with interleukin-1 (IL-1), c-kit ligand (KL; stem cell factor), and IL-3 and 2 weeks in liquid culture. Transduced colony-forming unit-granulocyte- macrophage (CFU-GM), assayed directly after the transduction procedure, were protected completely against 2 x 10(-8) mol/L MTX, a concentration that significantly reduced the CFU-GM detected in the control population. Gene transfer of the mutant DHFR led to a twofold selective advantage for a pre-CFU population after exposure to MTX in liquid culture (P < .001). Polybrene, in contrast with protamine, significantly inhibited the expansion of progenitors. The presence of proviral DNA was monitored by polymerase chain reaction (PCR) and was detected in greater than 80% of CFU-GM and ex vivo expanded pre-CFU. We have demonstrated that human hematopoietic precursor cells can be expanded extensively after retroviral gene transfer. The same population of early progenitors can be selected ex vivo with low-dose MTX. As long-term expression of transduced genes in human hematopoietic cells remains a problem in vivo, these results may have implications for future clinical trials, especially for the introduction of nonselectable genes.

Efficient protection from methotrexate toxicity and selection of transduced human hematopoietic cells following gene transfer of dihydrofolate reductase mutants

2003 ◽  
Vol 31 (12) ◽  
pp. 1215-1222 ◽  
Author(s):  
Roland Meisel ◽  
Walter Bardenheuer ◽  
Claudia Strehblow ◽  
Ursula Regina Sorg ◽  
Ahmet Elmaagacli ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Dihydrofolate Reductase ◽  
Hematopoietic Cells ◽  
Methotrexate Toxicity ◽  
Efficient Protection ◽  
Selection Of

Long-Term Follow-Up of Serially Transplanted Mice Receiving Extended Reduced Intensity Selection of MGMT-P140K Expressing Murine Repopulating Stem Cells Demonstrates Stable Oligo- to Polyclonal Hematopoiesis without Clonal Exhaustion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1286-1286
Author(s):  
Claudia Ball ◽  
Manfred Schmidt ◽  
Ingo Pilz ◽  
Monika Schrempp ◽  
Christof von Kalle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Gene Transfer ◽  
Blood Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Stem ◽  
Reduced Intensity ◽  
Selection Of

Abstract In vivo selection of gene modified hematopoietic stem cells permanently increases the relative proportion of blood cells that carry a therapeutic transgene despite initially low gene transfer efficiency, thereby decreasing the likelihood of insertional mutagenesis and avoiding the need of myeloablative conditioning regimens. P140K Mutant O6-methylguanine-DNA methyltransferase (MGMT) enzyme confers resistance to the combination of the MGMT inhibitor O(6)-benzylguanine (O(6)BG) and nitrosourea drugs such as 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU). We have previously shown that reduced intensity and toxicity BCNU/O6-BG selection allows efficient selection of MGMT-P140K expressing oligoclonal murine hematopoiesis. Nevertheless, whether long-term selection and the associated proliferative stress impairs long-term differentiation and proliferation of MGMT-P140K expressing stem cell clones is currently unknown and remains a major concern in the clinical application of MGMT selection. To address this question, serial transplantations of murine MGMT-P140K expressing hematopoiesis combined with repeated administrations of O6-BG and BCNU were done. After ex vivo gene transfer of an MGMT/IRES/eGFP encoding retroviral vector, bone marrow cells were transplanted into syngeneic C57 BL/6J mice and primary, secondary and tertiary recipient mice were subsequently treated every four weeks in order to exaggerate potential effects on long-term clonal behaviour. Lineage contribution of the transduced hematopoiesis was monitored by FACS over a total of 14 rounds of selection and clonality by LAM-PCR over a total of 12 rounds of selection. In primary mice the percentage of transduced blood cells increased from 4.7 ± 0.8 % to 36.4 ± 9.8 % (n=12) and in secondary mice from 29.9 ± 7.2 % to 65.1 ± 8.7 % (n=18) after selection without persisting peripheral blood cytopenia. Lineage analysis showed an unchanged multilineage differentiation potential of transduced cells in 1st, 2nd and 3rd generation animals. LAM PCR analysis of peripheral blood samples revealed stable oligo- to polyclonal hematopoiesis in primary and secondary mice. Evidence for predominant clones or clonal exhaustion was not observed despite up to 12 rounds of BCNU/O6-BG treatment. Interestingly, pairs of secondary transplanted mice that received bone marrow cells from identical donors showed very similar clonal composition, engraftment kinetics under selection and lineage contribution of the transduced hematopoiesis, indicating extensive self-renewal of transplantable stem cells in the primary mice resulting in a net symmetric refilling of the stem cell compartment. In summary, we demonstrate that even extended selection of MGMT-P140K expressing hematopoietic stem cells by repetitive chemotherapy does not affect their differentiation or proliferation potential and does not result in clonal exhaustion. Our results have important implications for the clinical use of MGMT selection strategies for the amplification of a limited number of gene corrected clones in clinical gene therapy.

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