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1.
Methods Mol Biol. 2017;1639:267-275. doi: 10.1007/978-1-4939-7163-3_27.

Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency.

Author information

1
Horae Gene Therapy Center, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA.
2
Horae Gene Therapy Center, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA. terry.flotte@umassmed.edu.
3
Department of Pediatrics, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA. terry.flotte@umassmed.edu.
4
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA. terry.flotte@umassmed.edu.

Abstract

This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

KEYWORDS:

CRISPR/Cas9; Emphysema; Genome editing; Liver disease; SERPINA1

PMID:
28752467
DOI:
10.1007/978-1-4939-7163-3_27
[Indexed for MEDLINE]
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2.
Mol Ther. 2017 Jun 7;25(6):1387-1394. doi: 10.1016/j.ymthe.2017.03.029. Epub 2017 Apr 10.

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

Author information

1
University of Massachusetts Medical School, Worcester, MA 01655, USA.
2
University of Massachusetts Medical School, Worcester, MA 01655, USA; Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
3
Department of Respiratory Research, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 2, Ireland.
4
Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
5
University of Florida College of Medicine, Gainesville, FL 32610, USA.
6
Applied Genetic Technologies Corporation, Alachua, FL 32615, USA.
7
Cincinnatti Children's Hospital, Cincinnati, OH 45229, USA.
8
University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: terry.flotte@umassmed.edu.

Abstract

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.

KEYWORDS:

A1AT; AAT; AAV; PD-1; Tregs; alpha-1 antitrypsin; clinical trial; exhausted T cells; gene therapy; rAAV

PMID:
28408179
PMCID:
PMC5474959
DOI:
10.1016/j.ymthe.2017.03.029
[Indexed for MEDLINE]
Free PMC Article
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3.
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1655-1659. doi: 10.1073/pnas.1617726114. Epub 2017 Jan 30.

Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency.

Author information

1
Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
2
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
4
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655.
5
Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; wilsonjm@upenn.edu.

Abstract

Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy.

KEYWORDS:

a-1-antitrypsin; adeno-associated virus; gene therapy; immune response; polymorphism

PMID:
28137880
PMCID:
PMC5320988
DOI:
10.1073/pnas.1617726114
[Indexed for MEDLINE]
Free PMC Article
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4.
Hum Gene Ther Methods. 2015 Jun;26(3):77-81. doi: 10.1089/hgtb.2015.086.

Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency.

Author information

1
1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, MA 01655.
2
2 Department of Pediatrics, University of Massachusetts Medical School , Worcester, MA 01655.
3
3 Microbiology & Physiologic Systems, University of Massachusetts Medical School , Worcester, MA 01655.

Abstract

The pathway to a clinical gene therapy product often involves many changes of course and strategy before obtaining successful results. Here we outline the methodologies, both clinical and preclinical, that went into developing a gene therapy approach to the treatment of alpha-1 antitrypsin deficiency lung disease using muscle-targeted recombinant adeno-associated virus. From initial gene construct development in mouse models through multiple rounds of safety and biodistribution studies in rodents, rabbits, and nonhuman primates to ultimate human trials, this review seeks to provide insight into what clinical translation entails and could thereby inform the process for future investigators.

PMID:
26067712
PMCID:
PMC4559188
DOI:
10.1089/hgtb.2015.086
[Indexed for MEDLINE]
Free PMC Article
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5.
Expert Opin Biol Ther. 2015 Mar;15(3):329-36. doi: 10.1517/14712598.2015.978854. Epub 2014 Nov 3.

Current status of gene therapy for α-1 antitrypsin deficiency.

Author information

1
University of Massachusetts Medical School, Gene Therapy Center, Department of Pediatrics , Suite 340 55 Lake Avenue North Worcester, MA 01655 , USA +1 508 856 2107 ; +1 508 856 8181 ; terry.flotte@umassmed.edu.

Abstract

INTRODUCTION:

As a common monogenic disease, α-1 antitrypsin (AAT) deficiency has undergone thorough investigation for the development of gene therapy. The most common pathology associated with AAT deficiency occurs in the lung, where the loss of function due to impaired secretion of mutant AAT prevents the inhibition of neutrophil elastase and leads to loss of elastin content from the alveolar interstitium.

AREAS COVERED:

Current treatment in the USA consists of recurrent intravenous protein replacement therapy to augment serum AAT levels. In an attempt to replace recurring treatments with a single dose of gene therapy, recombinant adenovirus, plasmid, and recombinant adeno-associated virus (rAAV) vectors have been investigated as vectors for transgene delivery.

EXPERT OPINION:

Large strides in gene therapy for AAT deficiency lung disease have led to the development of rAAV1-AAT capable of producing sustained serum AAT levels in clinical trials after intramuscular administration in humans at 3% of the target level. Further increases in levels are anticipated as limb perfusion targets greater muscle mass. The future roles of intrapleural and airway delivery, miRNA-expressing vectors, iPS cell platforms, and genome editing are anticipated.

KEYWORDS:

adeno-associated virus; emphysema; gene therapy; liver disease; vectors; α-1 antitrypsin

PMID:
25363251
DOI:
10.1517/14712598.2015.978854
[Indexed for MEDLINE]
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6.
COPD. 2013 Mar;10 Suppl 1:44-9. doi: 10.3109/15412555.2013.764978.

Gene-based therapy for alpha-1 antitrypsin deficiency.

Author information

1
Gene Therapy Center and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

Abstract

Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed for human use. Further enhancing the likelihood of success of gene therapy is the fact that the AAT coding sequence is relatively short and the protein appears to function primarily in the plasma and extracellular space. This means that AAT production from any cell or tissue capable of secreting it could be useful therapeutically for augmentation. Based on these considerations, attempts have been made to develop AAT therapies using nonviral gene transfer, gammaretrovirus, recombinant adenovirus (rAd), and recombinant adeno-associated virus (rAAV) vectors. These have resulted in three phase I clinical trials (one of cationic liposome, one of rAAV2, and one of rAAV1) and one phase II clinical trial (with rAAV1). The results of the latter trial, while promising, demonstrated levels were only 3 to 5% of the target range. This indicates the need to further increase the dose of the vector and/or to increase the levels to within the therapeutic range.

PMID:
23527792
DOI:
10.3109/15412555.2013.764978
[Indexed for MEDLINE]
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7.
Hum Mol Genet. 2011 Apr 15;20(R1):R87-92. doi: 10.1093/hmg/ddr156. Epub 2011 Apr 16.

Gene therapy for alpha-1 antitrypsin deficiency.

Author information

1
Gene Therapy Center and Department of Pediatrics, University of Massachusetts Medical School, S1-340, 55 Lake Avenue North, Worcester, MA 01655, USA. terry.flotte@umassmed.edu

Abstract

Alpha-1 antitrypsin (AAT) deficiency is a common single-gene disorder among Northern Europeans and North Americans. The carrier frequency for the common missense mutation (Z-AAT) ranges from 4% in the US to nearly 25% in the Republic of Ireland. Severe AAT deficiency (plasma levels below 11 μm) is most commonly associated with an adult-onset lung disease, with pan-acinar emphysema and airway inflammation, which is thought to be primarily owing to the loss of function of AAT in neutralizing neutrophil elastase and other pro-inflammatory enzymes. In 5-10% of patients, severe liver disease may develop. This may occur at any time from infancy to adulthood, and is thought to be owing to toxicity from the Z-AAT mutant protein that folds poorly and forms insoluble polymers within the hepatocyte, which is the primary site for AAT production. Thus, gene therapy for AAT lung disease is conceived of as augmentation of serum levels (a prolonged form of protein replacement, which is currently in use), while gene therapy for liver disease presents the problem of also having to downregulate the production of Z-AAT protein. Over the years, numerous strategies have been employed for the gene therapy of both AAT-deficient lung disease and liver disease. These will be reviewed with an emphasis on modalities that have reached clinical trials recently.

PMID:
21498872
PMCID:
PMC3095063
DOI:
10.1093/hmg/ddr156
[Indexed for MEDLINE]
Free PMC Article
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8.
Pharmacogenomics. 2007 Sep;8(9):1191-8.

The promise of gene therapy for the treatment of alpha-1 antitrypsin deficiency.

Author information

1
University of Florida, Nephrology Division, College of Medicine, FL, USA.

Abstract

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.

PMID:
17924834
DOI:
10.2217/14622416.8.9.1191
[Indexed for MEDLINE]
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