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Long-Term Correction Of Very Long-Chain Acyl-Coa Dehydrogenase Deficiency In Mice Using Aav9 Gene Therapy, Allison Keeler, Thomas Conlon, Glenn Walter, Huadong Zeng, Scott Shaffer, Fu Dungtao, Kirsten Erger, Travis Cossette, Qiushi Tang, Christian Mueller, Terence Flotte
Long-Term Correction Of Very Long-Chain Acyl-Coa Dehydrogenase Deficiency In Mice Using Aav9 Gene Therapy, Allison Keeler, Thomas Conlon, Glenn Walter, Huadong Zeng, Scott Shaffer, Fu Dungtao, Kirsten Erger, Travis Cossette, Qiushi Tang, Christian Mueller, Terence Flotte
Christian Mueller
Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 x 10(12) vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of …
Immune Responses In Cystic Fibrosis: Are They Intrinsically Defective?, Dmitry Ratner, Christian Mueller
Immune Responses In Cystic Fibrosis: Are They Intrinsically Defective?, Dmitry Ratner, Christian Mueller
Christian Mueller
Cystic fibrosis (CF), the most common lethal single-gene disorder affecting Northern Europeans and North Americans, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cftr is a chloride channel and a regulator of other ion channels, and many aspects of the CF phenotype are directly related to ion channel abnormalities attributable to CFTR mutation. Lung disease is the most common limitation to the quantity and quality of life for patients with CF. One aspect that continues to be enigmatic is the observed alterations in innate and adaptive immune responses to certain pathogens. Altered responses to Pseudomonas …
Gene Transfer In The Lung Using Recombinant Adeno-Associated Virus, Alisha Gruntman, Christian Mueller, Terence Flotte, Guangping Gao
Gene Transfer In The Lung Using Recombinant Adeno-Associated Virus, Alisha Gruntman, Christian Mueller, Terence Flotte, Guangping Gao
Christian Mueller
Adeno-associated virus (AAV) is a small replication-deficient DNA virus belonging to the Parvovirinae family. It has a single-stranded ∼4.7-kb genome. Recombinant AAV (rAAV) is created by replacing the viral rep and cap genes with the transgene of interest along with promoter and polyadenylation sequences. The short viral inverted terminal repeats must remain intact for replication and packaging in production, as well as vector genome processing and persistence in the transduction process. The AAV capsid (serotype) determines the tissue tropism of the rAAV vector. In this unit we will discuss serotype selection for lung targeting along with the factors effecting efficient …
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 …
The Pros And Cons Of Immunomodulatory Il-10 Gene Therapy With Recombinant Aav In A Cftr-/- -Dependent Allergy Mouse Model, Christian Mueller, Sofia Braag, A. Martino, Qiushi Tang, M. Campbell-Thompson, Terence Flotte
The Pros And Cons Of Immunomodulatory Il-10 Gene Therapy With Recombinant Aav In A Cftr-/- -Dependent Allergy Mouse Model, Christian Mueller, Sofia Braag, A. Martino, Qiushi Tang, M. Campbell-Thompson, Terence Flotte
Christian Mueller
Cystic fibrosis (CF) patients have decreased levels of lung epithelial interleukin (IL)-10 and increased levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-4, IL-8 and IL-6). This has also been documented in Cftr (cystic fibrosis transmembrane conductance regulator)-deficient mice (Cftr 489X(-/-), FABP-hCFTR(+/+)). Our laboratory has recently characterized a peculiar hyper-IgE phenotype in these mice, in response to Aspergillus fumigatus crude protein extract (Af-cpe). Thus, we hypothesized that sustained systemic circulating IL-10 levels achieved through skeletal muscle transduction with recombinant adeno-associated vectors expressing IL-10 (rAAV1-IL-10) would serve to downregulate Th1 and Th2 cytokine production. This in turn would dampen the allergic response …
Apparently Nonspecific Enzyme Elevations After Portal Vein Delivery Of Recombinant Adeno-Associated Virus Serotype 2 Vector In Hepatitis C Virus-Infected Chimpanzees, Terence Flotte, Jason Goetzmann, James Caridi, Joseph Paolillo, Thomas Conlon, Mark Potter, Christian Mueller, Barry Bryne
Apparently Nonspecific Enzyme Elevations After Portal Vein Delivery Of Recombinant Adeno-Associated Virus Serotype 2 Vector In Hepatitis C Virus-Infected Chimpanzees, Terence Flotte, Jason Goetzmann, James Caridi, Joseph Paolillo, Thomas Conlon, Mark Potter, Christian Mueller, Barry Bryne
Christian Mueller
Hepatic gene transfer is envisioned as a substitute for protein replacement therapies, many of which are derived from blood products. Thus, the target populations may have a high prevalence of blood-borne pathogens, such as hepatitis C virus (HCV). We sought to determine whether the safety of recombinant adeno-associated virus serotype 2 (rAAV2) would be altered by preexisting HCV infection. Doses of approximately 1 x 10(13) vector genomes of an rAAV2-chimpanzee alpha(1)-antitrypsin (rAAV2-cAAT) vector were injected into the portal vein of each of three HCV genome-positive (HCV+) chimpanzees and three HCV-negative (HCV-) controls. Acute safety studies were performed up to 90 …
Clinical Gene Therapy Using Recombinant Adeno-Associated Virus Vectors, Christian Mueller, Terence Flotte
Clinical Gene Therapy Using Recombinant Adeno-Associated Virus Vectors, Christian Mueller, Terence Flotte
Christian Mueller
Recombinant adeno-associated virus (rAAV) vectors possess a number of properties that may make them suitable for clinical gene therapy, including being based upon a virus for which there is no known pathology and a natural propensity to persist in human cells. Wild-type adeno-associated viruses (AAVs) are now known to be very diverse and ubiquitous in humans and nonhuman primates, which adds to the degree of confidence one may place in the natural history of AAV, namely that it has never been associated with any human tumors or other acute pathology, other than sporadic reports of having been isolated from spontaneously …
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 …
Partial Correction Of The Cftr-Dependent Abpa Mouse Model With Recombinant Adeno-Associated Virus Gene Transfer Of Truncated Cftr Gene, Christian Mueller, Daniel Torrez, Sofia Braag, Ashley Martino, Tracy Clarke, Martha Campbell-Thompson, Terence Flotte
Partial Correction Of The Cftr-Dependent Abpa Mouse Model With Recombinant Adeno-Associated Virus Gene Transfer Of Truncated Cftr Gene, Christian Mueller, Daniel Torrez, Sofia Braag, Ashley Martino, Tracy Clarke, Martha Campbell-Thompson, Terence Flotte
Christian Mueller
Recently, we have developed a model of airway inflammation in a CFTR knockout mouse utilizing Aspergillus fumigatus crude protein extract (Af-cpe) to mimic allergic bronchopulmonary aspergillosis (ABPA) 1, an unusual IgE-mediated hypersensitivity syndrome seen in up to 15% of cystic fibrosis (CF) patients and rarely elsewhere. We hypothesized that replacement of CFTR via targeted gene delivery to airway epithelium would correct aberrant epithelial cytokine signaling and ameliorate the ABPA phenotype in CFTR-deficient (CFTR 489X - /-, FABP-hCFTR + / +) mice. CFTR knockout mice underwent intra-tracheal (IT) delivery of recombinant adeno-associated virus serotype 5 (rAAV5Delta-264CFTR) or rAAV5-GFP at 2.58 x …
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 …
In Vivo Post-Transcriptional Gene Silencing Of Alpha-1 Antitrypsin By Adeno-Associated Virus Vectors Expressing Sirna, Pedro Cruz, Christian Mueller, Travis Cossette, Alexandra Golant, Qiushi Tang, Stuart Beattie, Mark Brantly, Martha Campbell-Thompson, Keith Blomenkamp, Jeffrey Teckman, Terence Flotte
In Vivo Post-Transcriptional Gene Silencing Of Alpha-1 Antitrypsin By Adeno-Associated Virus Vectors Expressing Sirna, Pedro Cruz, Christian Mueller, Travis Cossette, Alexandra Golant, Qiushi Tang, Stuart Beattie, Mark Brantly, Martha Campbell-Thompson, Keith Blomenkamp, Jeffrey Teckman, Terence Flotte
Christian Mueller
alpha-1 Antitrypsin (AAT) deficiency is one of the most common genetic diseases in North America, with a carrier frequency of approximately 4% in the US population. Homozygosity for the most common mutation (Glu342Lys, PI(*)Z) leads to the synthesis of a mutant protein, which accumulates and polymerizes within hepatocytes rather than being efficiently secreted. This lack of secretion causes severe serum deficiency predisposing to chronic lung disease. Twelve to fifteen percent of patients with PI(*)ZZ also develop liver disease, which can be severe, even in infancy. This is thought to be due to toxic effects of the accumulated mutant Z-AAT within …
The Promise Of Gene Therapy For The Treatment Of Alpha-1 Antitrypsin Deficiency, Pedro Cruz, Christian Mueller, Terence Flotte
The Promise Of Gene Therapy For The Treatment Of Alpha-1 Antitrypsin Deficiency, Pedro Cruz, Christian Mueller, Terence Flotte
Christian Mueller
In the last 13 years, three gene therapy trials for the treatment of alpha-1 antitrypsin deficiency have been conducted. The first trial delivered plasmid encoding the alpha-1 antitrypsin cDNA to the nasal epithelium using cationic liposomes. The last two trials delivered recombinant adeno-associated vectors encoding the alpha-1 antitrypsin cDNA by intramuscular injection. In this review, the progress of ongoing clinical trials and new gene therapy technologies is discussed.
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 …
Modulation Of Exaggerated-Ige Allergic Responses By Gene Transfer-Mediated Antagonism Of Il-13 And Il-17e., Christian Mueller, Allison Keeler, Sofia Braag, Timothy Menz, Qiushi Tang, Terence Flotte
Modulation Of Exaggerated-Ige Allergic Responses By Gene Transfer-Mediated Antagonism Of Il-13 And Il-17e., Christian Mueller, Allison Keeler, Sofia Braag, Timothy Menz, Qiushi Tang, Terence Flotte
Christian Mueller
Asthma and allergic rhinitis are almost invariable accompanied by elevated levels of immunoglobin E (IgE), and more importantly a genetic link between IgE levels and airway hyper-responsiveness has been established. We hypothesized that expression of soluble receptors directed against interleukin (IL)-13 and IL-17e would prevent the cytokines from engaging the cell-bound receptors and therefore help to attenuate allergic responses in a Cftr(-/-)-dependent mouse model of exaggerated-IgE responses. Cftr(-/-) mice were injected with recombinant adeno-associated virus 1 (rAAV1) intramuscularly expressing soluble receptors to IL-17e (IL-17Rh1fc) or IL-13 (IL-13Ralpha2Fc). Total IgE levels, in mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapy, were lower …
In Vitro And In Vivo Functional Characterization Of Gutless Recombinant Sv40-Derived Cftr Vectors, Christian Mueller, M. Strayer, Jeffrey Sirninger, Sofia Braag, Francisco Branco, Jean-Pierre Louboutin, Terence Flotte, David Strayer
In Vitro And In Vivo Functional Characterization Of Gutless Recombinant Sv40-Derived Cftr Vectors, Christian Mueller, M. Strayer, Jeffrey Sirninger, Sofia Braag, Francisco Branco, Jean-Pierre Louboutin, Terence Flotte, David Strayer
Christian Mueller
In cystic fibrosis (CF), respiratory failure caused by progressive airway obstruction and tissue damage is primarily a result of the aberrant inflammatory responses to lung infections with Pseudomonas aeruginosa. Despite considerable improvement in patient survival, conventional therapies are mainly supportive. Recent progress toward gene therapy for CF has been encouraging; however, several factors such as immune response and transduced cell turnover remain as potential limitations to CF gene therapy. As alternative gene therapy vectors for CF, we examined the feasibility of using recombinant SV40-derived vectors (rSV40s), which may circumvent some of these obstacles. To accommodate the large cystic fibrosis transmembrane …
Dual Reporter Comparative Indexing Of Raav Pseudotyped Vectors In Chimpanzee Airway, Terence Flotte, Anne Fischer, Jason Goetzmann, Christian Mueller, Liudmila Cebotaru, Ziying Yan, Lilli Wang, James Wilson, William Guggino, John Engelhardt
Dual Reporter Comparative Indexing Of Raav Pseudotyped Vectors In Chimpanzee Airway, Terence Flotte, Anne Fischer, Jason Goetzmann, Christian Mueller, Liudmila Cebotaru, Ziying Yan, Lilli Wang, James Wilson, William Guggino, John Engelhardt
Christian Mueller
Selecting the most efficient recombinant adeno-associated virus (rAAV) serotype for airway gene therapy has been difficult due to cross-specific differences in tropism and immune response between humans and animal models. Chimpanzees--the closest surviving genetic relative of humans--provide a valuable opportunity to select the most effective serotypes for clinical trials in humans. However, designing informative experiments using this protected species is challenging due to limited availability and experimental regulations. We have developed a method using Renilla luciferase (RL) and firefly luciferase (FL) reporters to directly index the relative transduction and immune response of two promising rAAV serotypes following lung coinfection. Analysis …
Gene Therapy For Cystic Fibrosis, Christian Mueller, Terence Flotte
Gene Therapy For Cystic Fibrosis, Christian Mueller, Terence Flotte
Christian Mueller
Cystic Fibrosis (CF) is an autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene that lead to defective ion transport in the conducting pulmonary airways and exocrine glands. Through a process that is not fully understood, CFTR defects predispose affected patients to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and Staphylococcus aureus. Following the discovery of the CFTR gene in 1989, CF became one of the primary targets for gene therapy research. Early enthusiasm surrounded the new field of gene therapy during most of the 1990s and it led academics and clinicians on …
Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence 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 Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence 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 10(10) vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar …