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Article: Predicted deleterious variants in the human genome relevant to gene therapy with adeno-associated virus vectors.

Rostami, Mahboubeh R / Leopold, Philip L / Vasquez, Jenifer M / de Mulder Rougvie, Miguel / Al Shakaki, Alya / Hssain, Ali Ait / Robay, Amal / Hackett, Neil R / Mezey, Jason G / Crystal, Ronald G

Molecular therapy. Methods & clinical development

2023 Volume 31, Page(s) 101136

Abstract: Based on the observation that humans have variable responses of gene expression with the same dose of an adeno-associated vector, we hypothesized that there are deleterious variants in genes coding for processes required for adeno-associated virus (AAV)- ... ...

Abstract	Based on the observation that humans have variable responses of gene expression with the same dose of an adeno-associated vector, we hypothesized that there are deleterious variants in genes coding for processes required for adeno-associated virus (AAV)-mediated gene transfer/expression that may hamper or enhance the effectiveness of AAV-mediated gene therapy. To assess this hypothesis, we evaluated 69,442 whole genome sequences from three populations (European, African/African American, and Qatari) for predicted deleterious variants in 62 genes known to play a role in AAV-mediated gene transfer/expression. The analysis identified 5,564 potentially deleterious mutations of which 27 were classified as common based on an allele frequency ≥1% in at least one population studied. Many of these deleterious variants are predicated to prevent while others enhance effective AAV gene transfer/expression, and several are linked to known hereditary disorders. The data support the hypothesis that, like other drugs, human genetic variability contributes to the person-to-person effectiveness of AAV gene therapy and the screening for genetic variability should be considered as part of future clinical trials.
Language	English
Publishing date	2023-10-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.101136
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Article ; Online: Identification of an exonic splicing silencer in exon 6A of the human VEGF gene

Crystal Ronald G / Wang Rui / Hackett Neil R

BMC Molecular Biology, Vol 10, Iss 1, p

2009 Volume 103

Abstract: Abstract Background The different isoforms of vascular endothelial growth factor (VEGF) play diverse roles in vascular growth, structure and function. Alternative splicing of the VEGF gene results in the expression of three abundant isoforms: VEGF121, ... ...

Abstract	Abstract Background The different isoforms of vascular endothelial growth factor (VEGF) play diverse roles in vascular growth, structure and function. Alternative splicing of the VEGF gene results in the expression of three abundant isoforms: VEGF121, VEGF165 and VEGF189. The mRNA for VEGF189 contains the alternatively spliced exon 6A whereas the mRNA for VEGF165 lacks this exon. The objective of this study was to identify the cis elements that control utilization of exon 6A. A reporter minigene was constructed (pGFP-E6A) containing the coding sequence for GFP whose translation was dependent on faithful splicing for removal of the VEGF exon 6A. To identify cis -acting splicing elements, sequential deletions were made across exon 6A in the pGFP-E6A plasmid. Results A candidate cis -acting exonic splicing silencer (ESS) comprising nucleotides 22-30 of exon 6A sequence was identified corresponding to the a silencer consensus sequence of AAGGGG. The function of this sequence as an ESS was confirmed in vivo both in the context of the reporter minigene as a plasmid and in the context of a longer minigene with VEGF exon 6A in its native context in an adenoviral gene transfer vector. Further mutagenesis studies resulted in the identification of the second G residue of the putative ESS as the most critical for function. Conclusion This work establishes the identity of cis sequences that regulate alternative VEGF splicing and dictate the relative expression levels of VEGF isoforms.
Keywords	Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Genetics ; QH426-470 ; Cytology ; QH573-671
Subject code	616
Language	English
Publishing date	2009-11-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Double-blinded, placebo-controlled, randomized gene therapy using surgery for vector delivery.

Crystal, Ronald G / Kaminsky, Stephen M / Hackett, Neil R / Rosengart, Todd K

Human gene therapy

2012 Volume 23, Issue 5, Page(s) 438–441

MeSH term(s)	Adenoviridae ; Coronary Artery Disease/surgery ; Coronary Artery Disease/therapy ; Double-Blind Method ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Placebos ; Randomized Controlled Trials as Topic ; Surgical Procedures, Operative ; Vascular Endothelial Growth Factor A/genetics
Chemical Substances	Placebos ; VEGFA protein, human ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2012-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2012.062
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Article ; Online: Identification of an exonic splicing silencer in exon 6A of the human VEGF gene.

Wang, Rui / Crystal, Ronald G / Hackett, Neil R

BMC molecular biology

2009 Volume 10, Page(s) 103

Abstract: Background: The different isoforms of vascular endothelial growth factor (VEGF) play diverse roles in vascular growth, structure and function. Alternative splicing of the VEGF gene results in the expression of three abundant isoforms: VEGF121, VEGF165 ... ...

Abstract	Background: The different isoforms of vascular endothelial growth factor (VEGF) play diverse roles in vascular growth, structure and function. Alternative splicing of the VEGF gene results in the expression of three abundant isoforms: VEGF121, VEGF165 and VEGF189. The mRNA for VEGF189 contains the alternatively spliced exon 6A whereas the mRNA for VEGF165 lacks this exon. The objective of this study was to identify the cis elements that control utilization of exon 6A. A reporter minigene was constructed (pGFP-E6A) containing the coding sequence for GFP whose translation was dependent on faithful splicing for removal of the VEGF exon 6A. To identify cis-acting splicing elements, sequential deletions were made across exon 6A in the pGFP-E6A plasmid. Results: A candidate cis-acting exonic splicing silencer (ESS) comprising nucleotides 22-30 of exon 6A sequence was identified corresponding to the a silencer consensus sequence of AAGGGG. The function of this sequence as an ESS was confirmed in vivo both in the context of the reporter minigene as a plasmid and in the context of a longer minigene with VEGF exon 6A in its native context in an adenoviral gene transfer vector. Further mutagenesis studies resulted in the identification of the second G residue of the putative ESS as the most critical for function. Conclusion: This work establishes the identity of cis sequences that regulate alternative VEGF splicing and dictate the relative expression levels of VEGF isoforms.
MeSH term(s)	Base Sequence ; Exons/genetics ; Genes, Reporter ; Genome, Human/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Mutagenesis ; RNA Splicing/genetics ; Reproducibility of Results ; Sequence Deletion ; Silencer Elements, Transcriptional/genetics ; Transfection ; Vascular Endothelial Growth Factor A/genetics
Chemical Substances	VEGFA protein, human ; Vascular Endothelial Growth Factor A ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2009-11-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1471-2199
ISSN (online)	1471-2199
DOI	10.1186/1471-2199-10-103
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Article ; Online: Airway basal cell vascular endothelial growth factor-mediated cross-talk regulates endothelial cell-dependent growth support of human airway basal cells.

Curradi, Giacomo / Walters, Matthew S / Ding, Bi-Sen / Rafii, Shahin / Hackett, Neil R / Crystal, Ronald G

Cellular and molecular life sciences : CMLS

2012 Volume 69, Issue 13, Page(s) 2217–2231

Abstract: The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory ...

Abstract	The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptome analysis of airway basal cells revealed high expression of vascular endothelial growth factor A (VEGFA), a gene not typically associated with the function of this cell type. Using cultures of primary human airway basal cells, we demonstrate that basal cells express all of the three major isoforms of VEGFA (121, 165 and 189) but lack functional expression of the classical VEGFA receptors VEGFR1 and VEGFR2. The VEGFA is actively secreted by basal cells and while it appears to have no direct autocrine function on basal cell growth and proliferation, it functions in a paracrine manner to activate MAPK signaling cascades in endothelium via VEGFR2-dependent signaling pathways. Using a cytokine- and serum-free co-culture system of primary human airway basal cells and human endothelial cells revealed that basal cell-secreted VEGFA activated endothelium to express mediators that, in turn, stimulate and support basal cell proliferation and growth. These data demonstrate novel VEGFA-mediated cross-talk between airway basal cells and endothelium, the purpose of which is to modulate endothelial activation and in turn stimulate and sustain basal cell growth.
MeSH term(s)	Blotting, Western ; Cell Proliferation ; Cells, Cultured ; DNA Primers/genetics ; Endothelial Cells/metabolism ; Endothelial Cells/physiology ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Profiling ; Humans ; Immunohistochemistry ; Paracrine Communication/physiology ; Protein Isoforms/metabolism ; Real-Time Polymerase Chain Reaction ; Receptor Cross-Talk/physiology ; Respiratory Mucosa/cytology ; Respiratory Mucosa/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	DNA Primers ; Protein Isoforms ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2012-03-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-012-0922-8
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Article ; Online: Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing

Sondhi, Dolan / Kaminsky, Stephen M / Hackett, Neil R / Pagovich, Odelya E / Rosenberg, Jonathan B / De, Bishnu P / Chen, Alvin / Van de Graaf, Benjamin / Mezey, Jason G / Mammen, Grace W / Mancenido, Denesy / Xu, Fang / Kosofsky, Barry / Yohay, Kaleb / Worgall, Stefan / Kaner, Robert J / Souwedaine, Mark / Greenwald, Bruce M / Kaplitt, Michael /

Dyke, Jonathan P / Ballon, Douglas J / Heier, Linda A / Kiss, Szilard / Crystal, Ronald G

Science translational medicine

2020 Volume 12, Issue 572

Abstract: Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in ... ...

Abstract	Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the
MeSH term(s)	Aminopeptidases/genetics ; Brain ; Child ; Dependovirus/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Genetic Therapy ; Humans ; Magnetic Resonance Imaging ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/therapy ; Tripeptidyl-Peptidase 1
Chemical Substances	Tripeptidyl-Peptidase 1 ; Aminopeptidases (EC 3.4.11.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-) ; TPP1 protein, human (EC 3.4.14.9)
Language	English
Publishing date	2020-12-24
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abb5413
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Article ; Online: Rapid/sustained anti-anthrax passive immunity mediated by co-administration of Ad/AAV.

De, Bishnu P / Hackett, Neil R / Crystal, Ronald G / Boyer, Julie L

Molecular therapy : the journal of the American Society of Gene Therapy

2008 Volume 16, Issue 1, Page(s) 203–209

Abstract: Achieving both immediate and sustained protection against diseases caused by bacterial toxins and extracellular pathogens is a challenge in developing biodefense therapeutics. We hypothesized that a single co-administration of an adenovirus (Ad) vector ... ...

Abstract	Achieving both immediate and sustained protection against diseases caused by bacterial toxins and extracellular pathogens is a challenge in developing biodefense therapeutics. We hypothesized that a single co-administration of an adenovirus (Ad) vector and an adeno-associated virus (AAV) vector, both expressing a pathogen-specific monoclonal antibody, would provide rapid, persistent passive immunotherapy against the pathogen. In order to test this strategy, we used the lethal toxin of Bacillus anthracis as a target of a monoclonal antibody directed against the protective antigen (PA) component of the toxin, using co-administration of an Ad vector encoding an anti-PA monoclonal antibody (AdalphaPA) and an AAV vector encoding an anti-PA monoclonal antibody (AAVrh.10alphaPA). As early as 1 day after co-administration of AdalphaPA and AAVrh.10alphaPA to mice, serum anti-PA antibody levels were detectable, and were sustained through 6 months. Importantly, animals that received both vectors were protected against toxin challenge as early as 1 day after administration and throughout the 6 month duration of the experiment. These data provide a new paradigm of genetic passive immunotherapy by co-administration of Ad and AAV vectors, each encoding a pathogen-specific monoclonal antibody, as an effective approach for both rapid and sustained protection against a bio-terror attack.
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/immunology ; Animals ; Anthrax/immunology ; Anthrax/prevention & control ; Anthrax Vaccines/administration & dosage ; Anthrax Vaccines/genetics ; Anthrax Vaccines/immunology ; Antibodies, Monoclonal/genetics ; Bacillus anthracis/immunology ; Dependovirus/genetics ; Dependovirus/immunology ; Drug Administration Schedule ; Gene Transfer Techniques ; Genetic Vectors/administration & dosage ; Genetic Vectors/immunology ; Humans ; Immunization, Passive ; Injections, Intravenous ; Male ; Mice ; Mice, Inbred C57BL ; Vaccines, Combined/administration & dosage ; Vaccines, Combined/genetics ; Vaccines, Combined/immunology
Chemical Substances	Anthrax Vaccines ; Antibodies, Monoclonal ; Vaccines, Combined
Language	English
Publishing date	2008-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/sj.mt.6300344
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Article ; Online: RFX3 modulation of FOXJ1 regulation of cilia genes in the human airway epithelium.

Didon, Lukas / Zwick, Rachel K / Chao, Ion Wa / Walters, Matthew S / Wang, Rui / Hackett, Neil R / Crystal, Ronald G

Respiratory research

2013 Volume 14, Page(s) 70

Abstract: Background: Ciliated cells play a central role in cleansing the airways of inhaled contaminants. They are derived from basal cells that include the airway stem/progenitor cells. In animal models, the transcription factor FOXJ1 has been shown to induce ... ...

Abstract	Background: Ciliated cells play a central role in cleansing the airways of inhaled contaminants. They are derived from basal cells that include the airway stem/progenitor cells. In animal models, the transcription factor FOXJ1 has been shown to induce differentiation to the ciliated cell lineage, and the RFX transcription factor-family has been shown to be necessary for, but not sufficient to induce, correct cilia development. Methods: To test the hypothesis that FOXJ1 and RFX3 cooperatively induce expression of ciliated genes in the differentiation process of basal progenitor cells toward a ciliated cell linage in the human airway epithelium, primary human airway basal cells were assessed under conditions of in vitro differentiation induced by plasmid-mediated gene transfer of FOXJ1 and/or RFX3. TaqMan PCR was used to quantify mRNA levels of basal, secretory, and cilia-associated genes. Results: Basal cells, when cultured in air-liquid interface, differentiated into a ciliated epithelium, expressing FOXJ1 and RFX3. Transfection of FOXJ1 into resting basal cells activated promoters and induced expression of ciliated cell genes as well as both FOXJ1 and RFX3, but not basal cell genes. Transfection of RFX3 induced expression of RFX3 but not FOXJ1, nor the expression of cilia-related genes. The combination of FOXJ1 + RFX3 enhanced ciliated gene promoter activity and mRNA expression beyond that due to FOXJ1 alone. Corroborating immunoprecipitation studies demonstrated an interaction between FOXJ1 and RFX3. Conclusion: FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells.
MeSH term(s)	Cell Differentiation ; Cells, Cultured ; Cilia/metabolism ; Cilia/ultrastructure ; DNA-Binding Proteins/metabolism ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation/physiology ; Humans ; Regulatory Factor X Transcription Factors ; Respiratory Mucosa/metabolism ; Respiratory Mucosa/ultrastructure ; Stem Cells/cytology ; Stem Cells/metabolism ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; FOXJ1 protein, human ; Forkhead Transcription Factors ; RFX3 protein, human ; Regulatory Factor X Transcription Factors ; Transcription Factors
Language	English
Publishing date	2013-07-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-9921
ISSN (online)	1465-993X
ISSN	1465-9921
DOI	10.1186/1465-9921-14-70
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Article ; Online: HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors.

Gao, Chuan / Tignor, Nicole L / Salit, Jacqueline / Strulovici-Barel, Yael / Hackett, Neil R / Crystal, Ronald G / Mezey, Jason G

Bioinformatics (Oxford, England)

2013 Volume 30, Issue 3, Page(s) 369–376

Abstract: Motivation: Identification of expression Quantitative Trait Loci (eQTL), the genetic loci that contribute to heritable variation in gene expression, can be obstructed by factors that produce variation in expression profiles if these factors are ... ...

Abstract	Motivation: Identification of expression Quantitative Trait Loci (eQTL), the genetic loci that contribute to heritable variation in gene expression, can be obstructed by factors that produce variation in expression profiles if these factors are unmeasured or hidden from direct analysis. Methods: We have developed a method for Hidden Expression Factor analysis (HEFT) that identifies individual and pleiotropic effects of eQTL in the presence of hidden factors. The HEFT model is a combined multivariate regression and factor analysis, where the complete likelihood of the model is used to derive a ridge estimator for simultaneous factor learning and detection of eQTL. HEFT requires no pre-estimation of hidden factor effects; it provides P-values and is extremely fast, requiring just a few hours to complete an eQTL analysis of thousands of expression variables when analyzing hundreds of thousands of single nucleotide polymorphisms on a standard 8 core 2.6 G desktop. Results: By analyzing simulated data, we demonstrate that HEFT can correct for an unknown number of hidden factors and significantly outperforms all related hidden factor methods for eQTL analysis when there are eQTL with univariate and multivariate (pleiotropic) effects. To demonstrate a real-world application, we applied HEFT to identify eQTL affecting gene expression in the human lung for a study that included presumptive hidden factors. HEFT identified all of the cis-eQTL found by other hidden factor methods and 91 additional cis-eQTL. HEFT also identified a number of eQTLs with direct relevance to lung disease that could not be found without a hidden factor analysis, including cis-eQTL for GTF2H1 and MTRR, genes that have been independently associated with lung cancer. Availability: Software is available at http://mezeylab.cb.bscb.cornell.edu/Software.aspx. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Gene Expression ; Gene Expression Profiling/methods ; Humans ; Lung/metabolism ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Regression Analysis ; Software
Language	English
Publishing date	2013-12-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btt690
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Article ; Online: Empirical Bayes conditional independence graphs for regulatory network recovery.

Mahdi, Rami / Madduri, Abishek S / Wang, Guoqing / Strulovici-Barel, Yael / Salit, Jacqueline / Hackett, Neil R / Crystal, Ronald G / Mezey, Jason G

Bioinformatics (Oxford, England)

2012 Volume 28, Issue 15, Page(s) 2029–2036

Abstract: Motivation: Computational inference methods that make use of graphical models to extract regulatory networks from gene expression data can have difficulty reconstructing dense regions of a network, a consequence of both computational complexity and ... ...

Abstract	Motivation: Computational inference methods that make use of graphical models to extract regulatory networks from gene expression data can have difficulty reconstructing dense regions of a network, a consequence of both computational complexity and unreliable parameter estimation when sample size is small. As a result, identification of hub genes is of special difficulty for these methods. Methods: We present a new algorithm, Empirical Light Mutual Min (ELMM), for large network reconstruction that has properties well suited for recovery of graphs with high-degree nodes. ELMM reconstructs the undirected graph of a regulatory network using empirical Bayes conditional independence testing with a heuristic relaxation of independence constraints in dense areas of the graph. This relaxation allows only one gene of a pair with a putative relation to be aware of the network connection, an approach that is aimed at easing multiple testing problems associated with recovering densely connected structures. Results: Using in silico data, we show that ELMM has better performance than commonly used network inference algorithms including GeneNet, ARACNE, FOCI, GENIE3 and GLASSO. We also apply ELMM to reconstruct a network among 5492 genes expressed in human lung airway epithelium of healthy non-smokers, healthy smokers and individuals with chronic obstructive pulmonary disease assayed using microarrays. The analysis identifies dense sub-networks that are consistent with known regulatory relationships in the lung airway and also suggests novel hub regulatory relationships among a number of genes that play roles in oxidative stress and secretion. Availability and implementation: Software for running ELMM is made available at http://mezeylab.cb.bscb.cornell.edu/Software.aspx. Contact: ramimahdi@yahoo.com or jgm45@cornell.edu Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Algorithms ; Bayes Theorem ; Computational Biology/methods ; Computer Simulation ; Gene Expression Profiling/methods ; Gene Regulatory Networks ; Humans ; Respiratory Mucosa/metabolism ; Software
Language	English
Publishing date	2012-06-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/bts312
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