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Articles 1 - 20 of 20
Full-Text Articles in Medicine and Health Sciences
Bridging From Intramuscular To Limb Perfusion Delivery Of Raav: Optimization In A Non-Human Primate Study, Alisha Gruntman, Gwladys Gernoux, Qiushi Tang, Guo-Jie Ye, Dave R. Knop, Gensheng Wang, Janet Benson, Kristen E. Coleman, Allison M. Keeler, Christian Mueller, Louis G. Chicoine, Jeffrey D. Chulay, Terence R. Flotte
Bridging From Intramuscular To Limb Perfusion Delivery Of Raav: Optimization In A Non-Human Primate Study, Alisha Gruntman, Gwladys Gernoux, Qiushi Tang, Guo-Jie Ye, Dave R. Knop, Gensheng Wang, Janet Benson, Kristen E. Coleman, Allison M. Keeler, Christian Mueller, Louis G. Chicoine, Jeffrey D. Chulay, Terence R. Flotte
Christian Mueller
Phase 1 and phase 2 gene therapy trials using intramuscular (IM) administration of a recombinant adeno-associated virus serotype 1 (rAAV1) for replacement of serum alpha-1 antitrypsin (AAT) deficiency have shown long-term (5-year) stable transgene expression at approximately 2% to 3% of therapeutic levels, arguing for the long-term viability of this approach to gene replacement of secreted serum protein deficiencies. However, achieving these levels required 100 IM injections to deliver 135 mL of vector, and further dose escalation is limited by the scalability of direct IM injection. To further advance the dose escalation, we sought to bridge the rAAV-AAT clinical development …
Survival Advantage Of Both Human Hepatocyte Xenografts And Genome-Edited Hepatocytes For Treatment Of Alpha-1 Antitrypsin Deficiency, Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A. Kay, Leonard D. Shultz, Dale L. Greiner, Terence R. Flotte, Michael A. Brehm, Christian Mueller
Survival Advantage Of Both Human Hepatocyte Xenografts And Genome-Edited Hepatocytes For Treatment Of Alpha-1 Antitrypsin Deficiency, Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A. Kay, Leonard D. Shultz, Dale L. Greiner, Terence R. Flotte, Michael A. Brehm, Christian Mueller
Christian Mueller
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create …
Hepatic Changes Associated With Chronic Alcohol Exposure In An Alpha-1 Antitrypsin Piz Mouse Model, Zhuoyao Lyu, Alisha M. Gruntman, Brian O'Sullivan-Murphy, Christian Mueller, Terence R. Flotte
Hepatic Changes Associated With Chronic Alcohol Exposure In An Alpha-1 Antitrypsin Piz Mouse Model, Zhuoyao Lyu, Alisha M. Gruntman, Brian O'Sullivan-Murphy, Christian Mueller, Terence R. Flotte
Christian Mueller
The PiZ mutation in the alpha-1 antitrypsin (AAT) gene causes the PiZ mutant protein to be sequestered in the endoplasmic reticulum of hepatocytes, causing significant liver pathology in ~10% of PiZZ homozygous AAT disease patients. Current transgenic mouse models of the disease include the liver-specific over-expression of mutant PiZ protein. However, these animal models do not efficiently recapitulate the liver damage found in PiZZ homozygous patients. Since only a small percentage of patients develop liver disease and it is not reproducible in animal models of AATD, it suggests that there are other factors that participate in disease pathogenesis. Here, we …
Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet Benson, Jeff Chulay, Dave Knop, Christian Mueller, Terence R. Flotte
Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet Benson, Jeff Chulay, Dave Knop, Christian Mueller, Terence R. Flotte
Christian Mueller
Alpha-one antitrypsin (AAT) deficiency is a genetic disease affecting the lungs due to inadequate anti-protease activity in the pulmonary interstitium. On-going human trials use intra-muscular delivery of adeno-associated virus (rAAV1), allowing expressing myofibers to secrete normal (M)AAT protein. In the Phase IIa trial, patients in the highest dose cohort (6x1012vg/kg) were given 100 intra-muscular (IM) injections of undiluted vector, with serum AAT levels still substantially below target levels. Previous work has shown that delivering rAAV vector to the musculature via limb perfusion leads to widespread gene expression in myofibers. We hypothesize that widespread delivery would result in an overall increase …
5 Year Expression And Neutrophil Defect Repair After Gene Therapy In Alpha-1 Antitrypsin Deficiency, Christian Mueller, Gwladys Gernoux, Alisha M. Gruntman, Florie Borel, Emer P. Reeves, Roberto Calcedo, Farshid N. Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis M. Messina, Jeffrey D. Chulay, Bruce Trapnell, James M. Wilson, Noel G. Mcelvaney, Terence R. Flotte
5 Year Expression And Neutrophil Defect Repair After Gene Therapy In Alpha-1 Antitrypsin Deficiency, Christian Mueller, Gwladys Gernoux, Alisha M. Gruntman, Florie Borel, Emer P. Reeves, Roberto Calcedo, Farshid N. Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis M. Messina, Jeffrey D. Chulay, Bruce Trapnell, James M. Wilson, Noel G. Mcelvaney, Terence R. Flotte
Christian Mueller
Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from …
Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz
Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz
Christian Mueller
Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with …
Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas J. Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence R. Flotte
Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas J. Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence R. Flotte
Christian Mueller
Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 1010 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar …
Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Christian Mueller
Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Christian Mueller
Christian Mueller
No abstract provided.
Self-Complementary Adeno-Associated Virus Vectors Improve Transduction Efficiency Of Corneal Endothelial Cells, Anja K. Gruenert, Marta Czugala, Christian Mueller, Marco Schmeer, Martin Schleef, Friedrich E. Kruse, Thomas A. Fuchsluger
Self-Complementary Adeno-Associated Virus Vectors Improve Transduction Efficiency Of Corneal Endothelial Cells, Anja K. Gruenert, Marta Czugala, Christian Mueller, Marco Schmeer, Martin Schleef, Friedrich E. Kruse, Thomas A. Fuchsluger
Christian Mueller
Transplantation of a donor cornea to restore vision is the most frequently performed transplantation in the world. Corneal endothelial cells (CEC) are crucial for the outcome of a graft as they maintain corneal transparency and avoid graft failure due to corneal opaqueness. Given the characteristic of being a monolayer and in direct contact with culture medium during cultivation in eye banks, CEC are specifically suitable for gene therapeutic approaches prior to transplantation. Recombinant adeno-associated virus 2 (rAAV2) vectors represent a promising tool for gene therapy of CEC. However, high vector titers are needed to achieve sufficient gene expression. One of …
Targeted Gene Delivery To The Enteric Nervous System Using Aav: A Comparison Across Serotypes And Capsid Mutants, Matthew J. Benskey, Nathan C. Kuhn, James J. Galligan, Joanna Garcia, Shannon E. Boye, William W. Hauswirth, Christian Mueller, Sanford L. Boye, Fredric P. Manfredsson
Targeted Gene Delivery To The Enteric Nervous System Using Aav: A Comparison Across Serotypes And Capsid Mutants, Matthew J. Benskey, Nathan C. Kuhn, James J. Galligan, Joanna Garcia, Shannon E. Boye, William W. Hauswirth, Christian Mueller, Sanford L. Boye, Fredric P. Manfredsson
Christian Mueller
Recombinant adeno-associated virus (AAV) vectors are one of the most widely used gene transfer systems in research and clinical trials. AAV can transduce a wide range of biological tissues, however to date, there has been no investigation on targeted AAV transduction of the enteric nervous system (ENS). Here, we examined the efficiency, tropism, spread, and immunogenicity of AAV transduction in the ENS. Rats received direct injections of various AAV serotypes expressing green fluorescent protein (GFP) into the descending colon. AAV serotypes tested included; AAV 1, 2, 5, 6, 8, or 9 and the AAV2 and AAV8 capsid mutants, AAV2-Y444F, AAV2-tripleY-F, …
Therapeutic Raavrh10 Mediated Sod1 Silencing In Adult Sod1(G93a) Mice And Nonhuman Primates, Florie Borel, Gwladys Gernoux, Brynn Cardozo, Jake P. Metterville, Gabriela Toro Cabrera, Lina Song, Qin Su, Guang Ping Gao, Mai K. Elmallah, Robert H. Brown Jr., Christian Mueller
Therapeutic Raavrh10 Mediated Sod1 Silencing In Adult Sod1(G93a) Mice And Nonhuman Primates, Florie Borel, Gwladys Gernoux, Brynn Cardozo, Jake P. Metterville, Gabriela Toro Cabrera, Lina Song, Qin Su, Guang Ping Gao, Mai K. Elmallah, Robert H. Brown Jr., Christian Mueller
Christian Mueller
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and …
Serum Levels Of Alpha-1 Antitrypsin Following Vascular Limb Or Intra-Muscular Delivery Of Aav1 Or Aav8 Gene Therapy Vectors In Rhesus Macaques, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet M. Benson, Jeffrey D. Chulay, David R. Knop, Christian Mueller, Terence R. Flotte
Serum Levels Of Alpha-1 Antitrypsin Following Vascular Limb Or Intra-Muscular Delivery Of Aav1 Or Aav8 Gene Therapy Vectors In Rhesus Macaques, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet M. Benson, Jeffrey D. Chulay, David R. Knop, Christian Mueller, Terence R. Flotte
Christian Mueller
Alpha-one antitrypsin (AAT) deficiency is a genetic disease that results in both lung disease and potentially liver failure in affected patients. In un-affected people AAT is produced in the liver and secreted to act as an anti-protease (primarily counteracting the effects of neutrophil elastase) in the lung. On-going human clinical trials have focused on intra-muscular delivery of adeno-associated virus (AAV1) to patients. The goal of delivery to the muscle is to have the myocytes serve as bio-factories to produce normal AAT protein and secrete it into the blood where it can exert its normal function in the lung. In the …
Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. Mcelvaney, Martha Campbell-Thompson, James M. Wilson
Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. Mcelvaney, Martha Campbell-Thompson, James M. Wilson
Christian Mueller
Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We previously reported achieving plasma wild-type (M) AAT concentrations at 2.5-3.8% of the therapeutic level at 1 year after intramuscular (IM) administration of 6×1012vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients, with an associated regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. Here, we report sustained expression at greater than 2% of the therapeutic level for 5 years after one-time treatment with rAAV1-AAT in …
Raav9 Airway Delivery Results In Effective Knockdown Of Mutant Alpha 1-Antitrypsin In The Liver While Upregulating Wildtype Alpha 1-Antitrypsin In The Lung, Alisha Gruntman, Christian Mueller, Qiushi Tang, Lina Song, James M. Wilson, Terence R. Flotte, Maria P. Limberis
Raav9 Airway Delivery Results In Effective Knockdown Of Mutant Alpha 1-Antitrypsin In The Liver While Upregulating Wildtype Alpha 1-Antitrypsin In The Lung, Alisha Gruntman, Christian Mueller, Qiushi Tang, Lina Song, James M. Wilson, Terence R. Flotte, Maria P. Limberis
Christian Mueller
Alpha 1-Antitrypsin (AAT) deficiency is a human genetic disease resulting in the production of mutant AAT, a hepatocyte produced serine protease inhibitor that functions to prevent alveolar epithelial damage by inhibiting neutrophil elastase. Patients with AAT deficiency have increased lung disease, due to decreased proteolytic protection, as well as sporadic severe liver disease secondary to accumulation of mutant AAT, especially a common mutant form termed PiZ, within hepatocytes. We previously showed, in a PiZ mutant mouse model, simultaneous knock-down of mutant PiZ-AAT and augmentation of wild-type AAT production through intravenous delivery of a recombinant adeno-associated viral (rAAV) vector encoding both …
Codon Optimization For Alpha 1-Antitrypsin Disease, Timothy Menz, Qiushi Tang, Lina Song, Christian Mueller, Terence R. Flotte
Codon Optimization For Alpha 1-Antitrypsin Disease, Timothy Menz, Qiushi Tang, Lina Song, Christian Mueller, Terence R. Flotte
Christian Mueller
Alpha 1-antitrypsin deficiency is a genetic disorder caused by defective production of alpha 1-antitrypsin (AAT). Gene therapy approaches have been conducted in patients with AAT deficiency with successful AAT expression, but not to the therapeutic levels required to reduce the risk of emphysema. Codon optimization, a somewhat new and evolving technique, is used by many scientists to maximize protein expression in living organisms by altering translational and transcriptional efficiency as well as protein refolding. The purpose of this study was to develop single stranded and double stranded AAT gene constructs, test their protein expression in vitro, and compare with those …
Phase 2 Clinical Trial Of A Recombinant Adeno-Associated Viral Vector Expressing Α1-Antitrypsin: Interim Results, Terence R. Flotte, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Roberto Calcedo, Farshid Rouhani, Martha Campbell-Thompson, Anthony T. Yachnis, Robert A. Sandhaus, Noel G. Mcelvaney, Christian Mueller, Louis M. Messina, James M. Wilson, Mark L. Brantly, David R. Knop, Guo-Jie Ye, Jeffrey D. Chulay
Phase 2 Clinical Trial Of A Recombinant Adeno-Associated Viral Vector Expressing Α1-Antitrypsin: Interim Results, Terence R. Flotte, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Roberto Calcedo, Farshid Rouhani, Martha Campbell-Thompson, Anthony T. Yachnis, Robert A. Sandhaus, Noel G. Mcelvaney, Christian Mueller, Louis M. Messina, James M. Wilson, Mark L. Brantly, David R. Knop, Guo-Jie Ye, Jeffrey D. Chulay
Christian Mueller
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with …
Induction Of Group Ivc Phospholipase A2 In Allergic Asthma: Transcriptional Regulation By Tnf-Α In Bronchoepithelial Cells, Justin S. Bickford, Kimberly J. Newsom, John-David Herlihy, Christian Mueller, Benjamin Keeler, Xiaolei Qiu, Jewell N. Walters, Nan Su, Shannon M. Wallet, Terence R. Flotte, Harry S. Nick
Induction Of Group Ivc Phospholipase A2 In Allergic Asthma: Transcriptional Regulation By Tnf-Α In Bronchoepithelial Cells, Justin S. Bickford, Kimberly J. Newsom, John-David Herlihy, Christian Mueller, Benjamin Keeler, Xiaolei Qiu, Jewell N. Walters, Nan Su, Shannon M. Wallet, Terence R. Flotte, Harry S. Nick
Christian Mueller
Airway inflammation in allergen-induced asthma is associated with eicosanoid release. These bioactive lipids exhibit anti- and pro-inflammatory activities with relevance to pulmonary pathophysiology. We hypothesized that sensitization/challenge using an extract from the ubiquitous fungus, Aspergillus fumigatus (Af), in a mouse model of allergic asthma would result in altered phospholipase gene expression, thus modulating the downstream eicosanoid pathway. We observed the most significant induction in the group IVC phospholipase A2 (cPLA2γ or PLA2G4C). Our results infer that Af extract can induce cPLA2γ levels directly in eosinophils while induction in lung epithelial cells is most likely a consequence of TNF-α secretion by …
Sustained Transgene Expression Despite T Lymphocyte Responses In A Clinical Trial Of Raav1-Aat Gene Therapy, Mark L. Brantly, Jeffrey D. Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L. Terry Spencer, Farshid Rouhani, Thomas J. Conlon, Roberto Calcedo, Michael R. Betts, Carolyn Spencer, Barry J. Bryne, James M. Wilson, Terence R. Flotte
Sustained Transgene Expression Despite T Lymphocyte Responses In A Clinical Trial Of Raav1-Aat Gene Therapy, Mark L. Brantly, Jeffrey D. Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L. Terry Spencer, Farshid Rouhani, Thomas J. Conlon, Roberto Calcedo, Michael R. Betts, Carolyn Spencer, Barry J. Bryne, James M. Wilson, Terence R. Flotte
Christian Mueller
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10(12), 2.2 x 10(13), and 6.0 x 10(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated …
Microrna-Regulated, Systemically Delivered Raav9: A Step Closer To Cns-Restricted Transgene Expression, Jun Xie, Qing Xie, Hongwei Zhang, Stefan L. Ameres, Jui-Hung Hung, Qin Su, Ran He, Xin Mu, Seemin Seher Ahmed, Soyeon Park, Hiroki Kato, Chengjian Li, Christian Mueller, Craig C. Mello, Zhiping Weng, Terence R. Flotte, Phillip D. Zamore, Guangping Gao
Microrna-Regulated, Systemically Delivered Raav9: A Step Closer To Cns-Restricted Transgene Expression, Jun Xie, Qing Xie, Hongwei Zhang, Stefan L. Ameres, Jui-Hung Hung, Qin Su, Ran He, Xin Mu, Seemin Seher Ahmed, Soyeon Park, Hiroki Kato, Chengjian Li, Christian Mueller, Craig C. Mello, Zhiping Weng, Terence R. Flotte, Phillip D. Zamore, Guangping Gao
Christian Mueller
Recombinant adeno-associated viruses (rAAVs) that can cross the blood-brain-barrier and achieve efficient and stable transvascular gene transfer to the central nervous system (CNS) hold significant promise for treating CNS disorders. However, following intravascular delivery, these vectors also target liver, heart, skeletal muscle, and other tissues, which may cause untoward effects. To circumvent this, we used tissue-specific, endogenous microRNAs (miRNAs) to repress rAAV expression outside the CNS, by engineering perfectly complementary miRNA-binding sites into the rAAV9 genome. This approach allowed simultaneous multi-tissue regulation and CNS-directed stable transgene expression without detectably perturbing the endogenous miRNA pathway. Regulation of rAAV expression by miRNA …
Sustained Mirna-Mediated Knockdown Of Mutant Aat With Simultaneous Augmentation Of Wild-Type Aat Has Minimal Effect On Global Liver Mirna Profiles, Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith S. Blomenkamp, Jeffrey H. Teckman, Lina Song, Phillip D. Zamore, Terence R. Flotte
Sustained Mirna-Mediated Knockdown Of Mutant Aat With Simultaneous Augmentation Of Wild-Type Aat Has Minimal Effect On Global Liver Mirna Profiles, Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith S. Blomenkamp, Jeffrey H. Teckman, Lina Song, Phillip D. Zamore, Terence R. Flotte
Christian Mueller
Alpha-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently …