5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency

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 years 1–5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated.

• Publication year

  2017

• Venue

  Molecular Therapy

• Publication date

  2017-04-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ymthe.2017.03.029PMID 28408179PMCID 5474959
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Dissociation of skeletal muscle for flow cytometric characterization of immune cells in macaques.

  2015cited by this paper
• Therapeutic Regulatory T Cells Subvert Effector T Cell Function in Inflamed Islets To Halt Autoimmune Diabetes

  2015cited by this paper
• Role of alpha‐1 antitrypsin in human health and disease

  2014cited by this paper
• The Circulating Proteinase Inhibitor α-1 Antitrypsin Regulates Neutrophil Degranulation and Autoimmunity

  2014cited by this paper
• Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression.

  2013cited by this paper
• Intrapleural Administration of an AAVrh.10 Vector Coding for Human α1-Antitrypsin for the Treatment of α1-Antitrypsin Deficiency

  2013cited by this paper
• Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles

  2012cited by this paper
• Phase 2 Clinical Trial of a Recombinant Adeno-Associated Viral Vector Expressing α1-Antitrypsin: Interim Results

  2011cited by this paper
• Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

  2009cited by this paper
• Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.

  2009cited by this paper
• Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Serotype 2 α1-Antitrypsin (AAT) Vector in AAT-Deficient Adults

  2006cited by this paper
• Intrapleural administration of a serotype 5 adeno-associated virus coding for alpha1-antitrypsin mediates persistent, high lung and serum levels of alpha1-antitrypsin.

  2004cited by this paper
• Intrapleural administration of a serotype 5 adeno-associated virus coding for α1-antitrypsin mediates persistent, high lung and serum levels of α1-antitrypsin

  2004cited by this paper
• Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: safety and immunologic aspects.

  2002cited by this paper
• Transfection of Nasal Mucosa with a Normal alpha1-Antitrypsin Gene in alpha1-Antitrypsin-Deficient Subjects: Comparison with Protein Therapy

  2000cited by this paper
• Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors.

  1998cited by this paper
• Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vector.

  1997cited by this paper
• Human α1-Antitrypsin Gene Transfer to In Vivo Mouse Hepatocytes

  1996cited by this paper
• Human alpha 1-antitrypsin gene transfer to in vivo mouse hepatocytes.

  1996cited by this paper
• Clinical Investigations: COPDAlpha1Antitrypsin Deficiency Deaths in the United States From 1979-1991: An Analysis Using Multiple-Cause Mortality Data

  1996cited by this paper
• Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vectors.

  1996cited by this paper
• Polarity of secretion of alpha 1-antitrypsin by human respiratory epithelial cells after adenoviral transfer of a human alpha 1-antitrypsin cDNA.

  1995cited by this paper
• Expression of human alpha 1-antitrypsin in mouse after in vivo gene transfer to hepatocytes by small liposomes.

  1994cited by this paper
• Aerosol and intravenous transfection of human alpha 1-antitrypsin gene to lungs of rabbits.

  1994cited by this paper
• Loop-sheet polymerization: the structural basis of Z alpha 1-antitrypsin accumulation in the liver.

  1994cited by this paper
• The mechanism of Z alpha 1-antitrypsin accumulation in the liver.

  1992cited by this paper

• Assessment of Immune Responses Against AAV Encoded Transgene Products

  2026cites this paper
• The co-delivery of Programmed Death 1 ligands enhances and prolongs rAAV-mediated gene expression in pre-immunized mice.

  2026cites this paper
• AAV yield, bioactivity, and particle heterogeneity are impacted by genome size and non-coding DNA elements

  2025cites this paper
• The curious case of AAV immunology.

  2025cites this paper
• A comprehensive analysis of scRNA-Seq and RNA-Seq unveils B cell immune suppression in the AAV-loaded brain

  2025cites this paper
• A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice

  2025cites this paper
• Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient

  2025cites this paper
• Development of an AAV-delivered microRNA gene therapy for myotonic dystrophy type 1

  2025cites this paper
• Prevalence Study of Cellular Capsid-Specific Immune Responses to AAV2, 4, 5, 8, 9, and rh10 in Healthy Donors

  2024cites this paper
• Alpha-1 Antitrypsin Deficiency in Children. A Modern View of the Problem

  2024cites this paper
• Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice

  2024cites this paper
• Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy

  2024cites this paper
• Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?

  2024cites this paper
• Recombinant Adeno-Associated Virus Vectors for Gene Therapy of the Central Nervous System: Delivery Routes and Clinical Aspects

  2024cites this paper
• Global seroprevalence of neutralizing antibodies against adeno-associated virus serotypes used for human gene therapies

  2024cites this paper
• Role of FoxP3+ Regulatory T Cells in Modulating Immune Responses to Adeno-Associated Virus Gene Therapy

  2024cites this paper
• Biodistribution and safety of a single rAAV3B-AAT vector for silencing and replacement of alpha-1 antitrypsin in Cynomolgus macaques

  2024cites this paper
• A strategy for high antibody expression with low anti-drug antibodies using AAV9 vectors

  2023cites this paper
• Viral Vectors in Gene Replacement Therapy

  2023cites this paper
• Identification of host essential factors for recombinant AAV transduction of the polarized human airway epithelium

  2023cites this paper
• Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice

  2023cites this paper
• Identification of Host Restriction Factors Critical for Recombinant AAV Transduction of Polarized Human Airway Epithelium

  2023cites this paper
• Combined Nano-Vector Mediated-Transfer to Suppress HIV-1 Infection with Targeted Antibodies in-vitro

  2023cites this paper
• Transcriptomic Analysis Reveals the Inability of Recombinant AAV8 to Activate Human Monocyte-Derived Dendritic Cells

  2023cites this paper
• Gene therapy for alpha-1 antitrypsin deficiency: an update

  2023cites this paper
• Durability of transgene expression after rAAV gene therapy

  2022cites this paper
• In vivo editing of the pan-endothelium by immunity evading simian adenoviral vector.

  2022cites this paper
• Meeting Summary: ESGCT 2022 AAV Safety Plenary Session

  2022cites this paper
• Progress in Respiratory Gene Therapy

  2022cites this paper
• Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

  2022cites this paper
• Secretion of functional α1-antitrypsin is cell type dependent: Implications for intramuscular delivery for gene therapy

  2022cites this paper
• Organoid transduction using recombinant adeno‐associated viral vectors: Challenges and opportunities

  2022cites this paper
• Using analogue data to substantiate long-term durability of gene therapies: a narrative review.

  2022cites this paper
• High‐level production of wild‐type and oxidation‐resistant recombinant alpha‐1‐antitrypsin in glycoengineered CHO cells

  2022cites this paper
• Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice

  2022cites this paper
• Development of an Adeno-Associated Virus-Vectored SARS-CoV-2 Vaccine and Its Immunogenicity in Mice

  2022cites this paper
• Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies

  2021cites this paper
• Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches

  2021cites this paper
• Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

  2021cites this paper
• Novel Combinatorial MicroRNA-Binding Sites in AAV Vectors Synergistically Diminish Antigen Presentation and Transgene Immunity for Efficient and Stable Transduction

  2021cites this paper
• Therapeutic Potential of Alpha-1 Antitrypsin in Type 1 and Type 2 Diabetes Mellitus

  2021cites this paper
• Adenine base editing reduces misfolded protein accumulation and toxicity in alpha-1 antitrypsin deficient patient iPSC-hepatocytes

  2021cites this paper
• Alpha1-antitrypsin deficiency: New therapies on the horizon.

  2021cites this paper
• Pulmonary transplantation of alpha-1 antitrypsin (AAT)-transgenic macrophages provides a source of functional human AAT in vivo

  2021cites this paper
• Pi*ZZ-related liver disease in children and adults—narrative review of the typical presentation and management of alpha-1 antitrypsin deficiency

  2021cites this paper
• Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells

  2021cites this paper
• Gene Therapy

  2021cites this paper
• Central and peripheral delivery of AAV9-SMN target different pathomechanisms in a mouse model of spinal muscular atrophy

  2021cites this paper
• Immune Responses to Adeno-Associated Virus-Mediated CRISPR Therapy

  2021cites this paper
• Encouraging and Unsettling Findings in Long-Term Follow-up of AAV Gene Transfer.

  2020cites this paper
• AAV vectors engineered to target insulin receptor greatly enhance intramuscular gene delivery

  2020cites this paper
• Alpha-1 antitrypsin deficiency and recombinant protein sources with focus on plant sources: updates, challenges and perspectives.

  2020cites this paper
• Methods of Purification and Application Procedures of Alpha1 Antitrypsin: A Long-Lasting History

  2020cites this paper
• Gene therapy for alpha 1-antitrypsin deficiency with an oxidant-resistant human alpha 1-antitrypsin

  2020cites this paper
• In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice

  2020cites this paper
• Gene Therapy in Rare Respiratory Diseases: What Have We Learned So Far?

  2020cites this paper
• Intramuscular injection of vectorized-scFvMC1 reduces pathological tau in two different tau transgenic models

  2020cites this paper
• Leveraging Population Genomics for Individualized Correction of the Hallmarks of Alpha-1 Antitrypsin Deficiency.

  2020cites this paper
• Advances in Alpha-1 Antitrypsin Gene Therapy.

  2020cites this paper
• Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

  2020cites this paper
• Delivery of genome-editing biomacromolecules for treatment of lung genetic disorders.

  2020cites this paper
• Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

  2020cites this paper
• Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

  2020cites this paper
• Engineering adeno-associated virus vectors for gene therapy

  2020cites this paper
• Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

  2020cites this paper
• AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

  2020cites this paper
• [Research progress of gene therapy in clinical application].

  2019cites this paper
• Future directions: diagnostic approaches and therapy with AAT

  2019cites this paper
• Gene Therapy for Pompe Disease: The Time is now

  2019cites this paper
• Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here?

  2019cites this paper
• Muscle-Directed Gene Therapy for Alpha-1 Antitrypsin Deficiency

  2019cites this paper
• Large-Scale Clinical Manufacturing of AAV Vectors for Systemic Muscle Gene Therapy

  2019cites this paper
• Toward In Vivo Gene Therapy Using CRISPR.

  2019cites this paper
• Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial

  2019cites this paper
• Adeno‐Associated Virus Delivery of Anti‐HIV Monoclonal Antibodies Can Drive Long‐Term Virologic Suppression

  2019cites this paper
• Five Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with No Detectable Immunity

  2019cites this paper
• Bridging from Intramuscular to Limb Perfusion Delivery of rAAV: Optimization in a Non-human Primate Study

  2019cites this paper
• Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

  2018cites this paper
• Intrapleural Gene Therapy for Alpha-1 Antitrypsin Deficiency-Related Lung Disease.

  2018cites this paper
• Pharmacology of Recombinant Adeno-associated Virus Production

  2018cites this paper
• Gene Delivery of Alpha-1-Antitrypsin Using Recombinant Adeno-Associated Virus (rAAV).

  2018cites this paper
• Lessons learned from lung and liver in-vivo gene therapy: implications for the future

  2018cites this paper
• Alpha-1 Antitrypsin Therapy for Autoimmune Disorders.

  2018cites this paper
• Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

  2018cites this paper
• Phospholipid transfer protein and alpha-1 antitrypsin regulate Hck kinase activity during neutrophil degranulation

  2018cites this paper
• Gene Therapy With Regulatory T Cells: A Beneficial Alliance

  2018cites this paper
• In Vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency

  2018cites this paper
• CRISPR‐Cas9 genome engineering: Treating inherited retinal degeneration

  2018cites this paper
• Amelioration of Alpha-1 Antitrypsin Deficiency Diseases with Genome Editing in Transgenic Mice

  2018cites this paper
• Gene therapy clinical trials worldwide to 2017: An update

  2018cites this paper
• Assessment of Humoral, Innate, and T-Cell Immune Responses to Adeno-Associated Virus Vectors

  2018cites this paper
• Regulatory and Exhausted T Cell Responses to AAV Capsid

  2017cites this paper
• Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial

  2017cites this paper
• Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions

  2017cites this paper
• Prevalence study of cellular capsid-specific immune responses to AAV1, 2, 4, 5, 8, 9 and rh10 reveals particular features for AAV9

  year unknowncites this paper