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Article ; Online: Gene-directed enzyme prodrug therapy for cancer: a glimpse into the future?

Both, Gerald W

Discovery medicine

2009 Volume 8, Issue 42, Page(s) 97–103

Abstract: Gene-directed enzyme prodrug therapy offers a new approach to treating some cancers. Clinical trials have been completed for brain and prostate cancers and the first product for post-surgical treatment of some brain tumors is awaiting marketing approval. ...

Abstract	Gene-directed enzyme prodrug therapy offers a new approach to treating some cancers. Clinical trials have been completed for brain and prostate cancers and the first product for post-surgical treatment of some brain tumors is awaiting marketing approval. Recent innovations provide a glimpse into the possible future evolution of a new gene medicine.
MeSH term(s)	Genetic Vectors/genetics ; Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Prodrugs/metabolism
Chemical Substances	Prodrugs
Language	English
Publishing date	2009-10
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1944-7930
ISSN (online)	1944-7930
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Article ; Online: Recent progress in gene-directed enzyme prodrug therapy: an emerging cancer treatment.

Both, Gerald W

Current opinion in molecular therapeutics

2009 Volume 11, Issue 4, Page(s) 421–432

Abstract: The principle of gene-directed enzyme prodrug therapy (GDEPT) has existed for many years but, while simple in concept, the effective practical application of this therapy has proven to be challenging. Improvements in the efficacy of GDEPT have been ... ...

Abstract	The principle of gene-directed enzyme prodrug therapy (GDEPT) has existed for many years but, while simple in concept, the effective practical application of this therapy has proven to be challenging. Improvements in the efficacy of GDEPT have been achieved principally through the choice and development of more effective vectors, by optimizing and controlling gene expression and by increasing the activity of the delivered enzyme through mutation. While innovation continues in this field, the pioneering GDEPT systems designed to treat glioma and prostate cancer have completed or are now entering late-stage clinical trials, respectively. As the pace of innovation in GDEPT technology far exceeds its clinical application, these initial products are anticipated to be replaced by next-generation biologicals. This review highlights recent progress in the strategies and development of GDEPT and summarizes the status of current clinical trials. With the first GDEPT product for treatment of resected gliomas poised to gain marketing approval, a new era in cancer gene medicine is emerging.
MeSH term(s)	Animals ; Enzymes/metabolism ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy/trends ; Humans ; Neoplasms/drug therapy ; Prodrugs/metabolism ; Prodrugs/therapeutic use
Chemical Substances	Enzymes ; Prodrugs
Language	English
Publishing date	2009-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2022273-7
ISSN	2040-3445 ; 1464-8431
ISSN (online)	2040-3445
ISSN	1464-8431
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Zs.A 5272: Show issues

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Article ; Online: Association of Plasma Zinc and Copper with Body Composition, Lipids and Inflammation in a Cross-Sectional General Population Sample from Germany.

Övermöhle, Cara / Rimbach, Gerald / Waniek, Sabina / Strathmann, Eike A / Liedtke, Tatjana / Stürmer, Paula / Both, Marcus / Weber, Katharina S / Lieb, Wolfgang

Nutrients

2023 Volume 15, Issue 20

Abstract: We aimed to relate circulating plasma zinc and copper to a broad spectrum of adiposity-related traits in a cross-sectional Northern German study (n = 841, 42% female, age: 61 ± 12 years). Zinc and copper were measured by inductively coupled plasma-mass ... ...

Abstract	We aimed to relate circulating plasma zinc and copper to a broad spectrum of adiposity-related traits in a cross-sectional Northern German study (n = 841, 42% female, age: 61 ± 12 years). Zinc and copper were measured by inductively coupled plasma-mass spectrometry. Subcutaneous (SAT) and visceral (VAT) adipose tissue and liver fat were derived from 534 and 538 participants, respectively, via magnet resonance imaging. Associations were assessed using multivariable-adjusted linear regression analysis. An increase per one standard deviation (SD) in zinc was associated with direct linear increases in body mass index (BMI) (1.17%; 95% confidence interval (95%CI) 0.15-2.20%), waist circumference (0.85%; 95%CI 0.04-1.67%) and waist-to-hip ratio (0.64%; 95%CI 0.18-1.09%). A 1-SD increment in copper was directly associated with BMI (1.64%; 0.41-2.88%) and waist circumference (1.22%; 95%CI 0.25-2.20%) but not waist-to-hip ratio. Independent of fat intake, zinc displayed associations with VAT (5.73%; 95%CI 2.04-9.56%) and with liver fat (3.84%; 95%CI 1.49-6.25%), the latter association being also independent of BMI. Copper was directly associated with SAT (4.64%; 95%CI 0.31-9.15%) before accounting for BMI, but showed no association with VAT or liver fat. Observed associations suggest a possible relevance of zinc and copper to adiposity. Particularly zinc displayed associations with traits of abdominal adiposity and liver fat.
MeSH term(s)	Humans ; Female ; Middle Aged ; Aged ; Male ; Copper/metabolism ; Cross-Sectional Studies ; Zinc/metabolism ; Intra-Abdominal Fat/metabolism ; Obesity/metabolism ; Adiposity ; Inflammation/metabolism ; Body Composition ; Body Mass Index ; Waist Circumference ; Lipids
Chemical Substances	Copper (789U1901C5) ; Zinc (J41CSQ7QDS) ; Lipids
Language	English
Publishing date	2023-10-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15204460
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Article: Ovine atadenovirus: a review of its biology, biosafety profile and application as a gene delivery vector.

Both, Gerald W

Immunology and cell biology

2004 Volume 82, Issue 2, Page(s) 189–195

Abstract: The ovine adenovirus isolate OAdV287 is the prototype of the newly recognized genus of atadenoviruses. Although not as well studied as human mastadenoviruses, a substantial amount of work has now been carried out with this virus and an understanding of ... ...

Abstract	The ovine adenovirus isolate OAdV287 is the prototype of the newly recognized genus of atadenoviruses. Although not as well studied as human mastadenoviruses, a substantial amount of work has now been carried out with this virus and an understanding of its interesting and unique properties is beginning to emerge. In this article the biology and biosafety profile of the virus is reviewed. This knowledge underpins the exploitation of the virus as a gene delivery vector. Its potential as a vaccine vector and its application to the treatment of prostate cancer is summarized and discussed.
MeSH term(s)	Adenoviridae/metabolism ; Animals ; Genetic Therapy ; Genetic Vectors ; Humans ; Male ; Promoter Regions, Genetic ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/immunology ; RNA/metabolism ; Sheep/immunology ; Sheep/virology
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2004-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1046/j.0818-9641.2004.01223.x
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Article: Identification of a unique family of F-box proteins in atadenoviruses.

Both, Gerald W

Virology

2002 Volume 304, Issue 2, Page(s) 425–433

Abstract: Ovine adenovirus isolate 287 (OAdV-7) is the prototype of the atadenoviruses, a genus whose strategy for infection and replication is still being elucidated. A transcription unit at the right end of the genome contains four related genes (ORFs RH1, 2, 4, ...

Abstract	Ovine adenovirus isolate 287 (OAdV-7) is the prototype of the atadenoviruses, a genus whose strategy for infection and replication is still being elucidated. A transcription unit at the right end of the genome contains four related genes (ORFs RH1, 2, 4, and 6), at least three of which are nonessential for replication in vitro. Related genes are also present in the genomes of bovine and avian atadenoviruses. To investigate how these apparently redundant genes are decoded, a more detailed transcription map of the right end of the OAdV-7 genome has been deduced. Eight transcripts that were derived from a promoter in the terminal repeat sequence were identified. Five were potentially bicistronic. The transcripts could encode all the potential proteins of the region subject to efficient reinitiation of translation. However, the most interesting and surprising finding in this work was that the related RH proteins carry an F-box motif. This was first identified in OAdV-7 RH1 and subsequently found in RH2, 4, and 6 proteins and the related reading frames from the bovine and avian atadenoviruses. Although very rare among viral proteins, several hundred cellular proteins contain F-box motifs. F-box proteins facilitate the degradation of a variety of important regulatory proteins via SCF ubiquitin ligase complexes. Thus, it appears that atadenoviruses have adopted a strategy to regulate a key cellular pathway(s) that distinguishes them from the other adenovirus genera and from most viruses in general.
MeSH term(s)	Adenoviridae/genetics ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Genome, Viral ; Molecular Sequence Data ; Open Reading Frames ; Peptide Synthases/physiology ; Promoter Regions, Genetic ; SKP Cullin F-Box Protein Ligases ; Sheep ; Transcription, Genetic ; Viral Proteins/physiology
Chemical Substances	Viral Proteins ; SKP Cullin F-Box Protein Ligases (EC 2.3.2.27) ; Peptide Synthases (EC 6.3.2.-)
Language	English
Publishing date	2002-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1006/viro.2002.1734
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Article ; Online: Xenogenic Adenoviral Vectors

Both, Gerald W.

Adenoviral Vectors for Gene Therapy

Abstract: This chapter discusses the utility and safety of xenogenic vectors for vaccination or gene delivery. The properties and behavior of these vectors in heterologous situations are also discussed. Ideally, vectors for gene transfer into human cells should be ...

Abstract	This chapter discusses the utility and safety of xenogenic vectors for vaccination or gene delivery. The properties and behavior of these vectors in heterologous situations are also discussed. Ideally, vectors for gene transfer into human cells should be capable of transgene expression without replication or detrimental expression of viral genes. Infection of human cell lines with intact xenogenic adenoviruses established the principle that these viruses are replication defective at the inputs tested, although the molecular basis for defective replication is not understood. Most work with xenogenic vectors is still firmly based in the laboratory and while this is appropriate to demonstrate the utility of a vector the amount of work required for eventual exploitation of a vector in the clinic should not be underestimated. Understanding the biology of these vectors will ultimately lead to an increased choice of gene delivery vectors, providing more options in therapeutic strategy and design.
Keywords	covid19
Publisher	PMC
Document type	Article ; Online
DOI	10.1016/b978-012199504-1/50017-1
Database	COVID19

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Article ; Online: Chapter 16 Xenogenic Adenoviral Vectors

Both, Gerald W.

Adenoviral Vectors for Gene Therapy

Abstract: Publisher Summary This chapter discusses the utility and safety of xenogenic vectors for vaccination or gene delivery. The properties and behavior of these vectors in heterologous situations are also discussed. Ideally, vectors for gene transfer into ... ...

Abstract	Publisher Summary This chapter discusses the utility and safety of xenogenic vectors for vaccination or gene delivery. The properties and behavior of these vectors in heterologous situations are also discussed. Ideally, vectors for gene transfer into human cells should be capable of transgene expression without replication or detrimental expression of viral genes. Infection of human cell lines with intact xenogenic adenoviruses established the principle that these viruses are replication defective at the inputs tested, although the molecular basis for defective replication is not understood. Most work with xenogenic vectors is still firmly based in the laboratory and while this is appropriate to demonstrate the utility of a vector the amount of work required for eventual exploitation of a vector in the clinic should not be underestimated. Understanding the biology of these vectors will ultimately lead to an increased choice of gene delivery vectors, providing more options in therapeutic strategy and design.
Keywords	covid19
Publisher	Elsevier; PMC
Document type	Article ; Online
DOI	10.1016/b978-012199504-1/50017-1
Database	COVID19

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Article: Complementation of a defective human adenovirus by an otherwise incompatible ovine adenovirus recombinant carrying a functional E1A gene.

Lockett, Linda J / Both, Gerald W

Virology

2002 Volume 294, Issue 2, Page(s) 333–341

Abstract: All known human adenoviruses are classified as mastadenoviruses, while the ovine adenovirus (OAdV) serotype 7 is the prototype of the atadenoviruses, a proposed new genus. OAdV replicates abortively in human cell types and has potential as a gene ... ...

Abstract	All known human adenoviruses are classified as mastadenoviruses, while the ovine adenovirus (OAdV) serotype 7 is the prototype of the atadenoviruses, a proposed new genus. OAdV replicates abortively in human cell types and has potential as a gene transfer vector. However, the function of OAdV nonstructural genes is poorly understood and it is unclear whether OAdV replication might be complemented by a replicating human AdV in coinfected cells. To investigate possible interactions three human cell lines were singly infected with OAdV or human AdV5 or doubly infected. The development of a cytopathic effect and genome replication was monitored over three passages in each cell type. No significant OAdV replication occurred in any of the cell types examined either in the presence or in the absence of replicating AdV5. No aberrant AdV5 genome products were detected in coinfected cells. In contrast, in coinfected cells an OAdV recombinant that expressed the AdV5 E1A gene was able to promote the replication of an AdV5 E1A-deficient mutant, demonstrating trans-complementation between appropriate viruses. These findings have implications for the biosafety of OAdV vectors and their possible utility for enhancing gene delivery.
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/physiology ; Adenovirus E1A Proteins/genetics ; Adenovirus E1A Proteins/physiology ; Adenoviruses, Human/genetics ; Adenoviruses, Human/physiology ; Animals ; Defective Viruses/genetics ; Defective Viruses/physiology ; Gene Expression ; HeLa Cells ; Humans ; Mutagenesis ; Recombination, Genetic ; Sheep/virology ; Tumor Cells, Cultured ; Virus Replication
Chemical Substances	Adenovirus E1A Proteins
Language	English
Publishing date	2002-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1006/viro.2001.1327
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Article ; Online: Potent antietumor immunity in mice induced by vaccination with an ovine atadenovirus vector.

Tang, Rongying / Li, Kunyu / Wilson, Michelle / Both, Gerald W / Taylor, John A / Young, Sarah L

Journal of immunotherapy (Hagerstown, Md. : 1997)

2012 Volume 35, Issue 1, Page(s) 32–41

Abstract: Identification of adenoviral isolates of nonhuman origin has fostered development of vectors with potential to overcome preexisting immunity in the human population that may affect clinical applications. Ovine adenoviral isolate, OAdV287 (OAdV7), the ... ...

Abstract	Identification of adenoviral isolates of nonhuman origin has fostered development of vectors with potential to overcome preexisting immunity in the human population that may affect clinical applications. Ovine adenoviral isolate, OAdV287 (OAdV7), the prototype of the genus Atadenovirus, has been previously characterized as a gene delivery vector although the receptor(s) used for infection remain to be identified. Here, we report the first use of recombinant OAdV7 as a vaccine for inducing an antitumor immune response in a mouse model. Treatment of murine BMDC with OAdV7 vectors expressing ovalbumin (OVA) resulted in upregulation of costimulatory markers and production of IL-12. Splenocytes isolated from immunized mice responded to antigen restimulation in vitro by proliferation and production of IFNγ. In vivo cytotoxicity assays revealed efficient killing of antigenic peptide-pulsed target cells 1 week after immunization, with an average killing efficiency of 75%. In mice inoculated with B16-OVA tumor cells immunization with OAdV7-OVA retarded and essentially prevented tumor growth in prophylactic and therapeutic tumor trials, respectively. Generation of a robust memory response was confirmed on tumor rechallenge in the prophylactic model. Therefore, OAdV7 is a novel vector with potential for further development of tumor vaccines.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Atadenovirus/immunology ; Cell Differentiation/immunology ; Cell Proliferation ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/pathology ; Dendritic Cells/virology ; Genetic Vectors ; Immunization ; Immunologic Memory ; Interferon-gamma/metabolism ; Interleukin-12/metabolism ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Melanoma, Experimental/therapy ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Ovalbumin/genetics ; Ovalbumin/immunology ; Sheep ; Tumor Burden
Chemical Substances	Antigens, Neoplasm ; Interleukin-12 (187348-17-0) ; Interferon-gamma (82115-62-6) ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2012-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1064067-8
ISSN	1537-4513 ; 1053-8550 ; 1524-9557
ISSN (online)	1537-4513
ISSN	1053-8550 ; 1524-9557
DOI	10.1097/CJI.0b013e318238a115
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Zs.A 1778: Show issues

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Article ; Online: Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results.

Gerald, Brittany / Ramsey, Keri / Belnap, Newell / Szelinger, Szabolcs / Siniard, Ashley L / Balak, Chris / Russell, Megan / Richholt, Ryan / De Both, Matt / Claasen, Ana M / Schrauwen, Isabelle / Huentelman, Matthew J / Craig, David W / Rangasamy, Sampathkumar / Narayanan, Vinodh

Seminars in pediatric neurology

2017 Volume 26, Page(s) 28–32

Abstract: Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or ... ...

Abstract	Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.
MeSH term(s)	Child, Preschool ; Diagnosis, Differential ; Diagnostic Errors ; Female ; GTP-Binding Protein alpha Subunits, Gi-Go/genetics ; Humans ; Methyl-CpG-Binding Protein 2/genetics ; Phenotype ; Rett Syndrome/diagnosis ; Rett Syndrome/genetics ; Spasms, Infantile/diagnosis ; Spasms, Infantile/genetics
Chemical Substances	GNAO1 protein, human ; MECP2 protein, human ; Methyl-CpG-Binding Protein 2 ; GTP-Binding Protein alpha Subunits, Gi-Go (EC 3.6.5.1)
Language	English
Publishing date	2017-08-16
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1290000-x
ISSN	1558-0776 ; 1071-9091
ISSN (online)	1558-0776
ISSN	1071-9091
DOI	10.1016/j.spen.2017.08.008
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