In Vivo Gene Therapy with Adeno-Associated Virus Vectors for Cystic Fibrosis

1997 ◽  
pp. 85-101 ◽  
Author(s):  
Terence R. Flotte ◽  
Barrie J. Carter
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Adeno Associated Virus ◽  
Virus Vectors

Adeno-associated virus vectors for human gene therapy

Gene Therapy ◽  
2020 ◽  
pp. 77-92
Author(s):  
Jeffrey S. Bartlett ◽  
Richard J. Samulski
Keyword(s):  
Gene Therapy ◽  
Human Gene ◽  
Adeno Associated Virus ◽  
Human Gene Therapy ◽  
Virus Vectors

In Vivo Potency Assay for Adeno-Associated Virus–Based Gene Therapy Vectors Using AAVrh.10 as an Example

2018 ◽  
Vol 29 (3) ◽  
pp. 146-155 ◽  
Author(s):  
Bishnu P. De ◽  
Alvin Chen ◽  
Christiana O. Salami ◽  
Benjamin Van de Graaf ◽  
Jonathan B. Rosenberg ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Potency Assay ◽  
Adeno Associated Virus ◽  
Gene Therapy Vectors

Capsid-Engineering for Central Nervous System-Directed Gene Therapy with Adeno-Associated Virus Vectors

2021 ◽  
Vol 32 (19-20) ◽  
pp. 1096-1119
Author(s):  
Josephine Macdonald ◽  
Jennifer Marx ◽  
Hildegard Büning
Keyword(s):  
Gene Therapy ◽  
Central Nervous System ◽  
Nervous System ◽  
Adeno Associated Virus ◽  
Virus Vectors

Engineering adeno-associated virus vectors for gene therapy

2020 ◽  
Vol 21 (4) ◽  
pp. 255-272 ◽  
Author(s):  
Chengwen Li ◽  
R. Jude Samulski
Keyword(s):  
Gene Therapy ◽  
Adeno Associated Virus ◽  
Virus Vectors

scholarly journals Nanotechnology and adeno-associated virus-based decorin gene therapy ameliorates peritoneal fibrosis

2014 ◽  
Vol 307 (7) ◽  
pp. F777-F782 ◽  
Author(s):  
Kunal Chaudhary ◽  
Harold Moore ◽  
Ashish Tandon ◽  
Suneel Gupta ◽  
Ramesh Khanna ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mesothelial Cell ◽  
Peritoneal Fibrosis ◽  
Tissue Samples ◽  
Adeno Associated Virus ◽  
Peritoneal Tissue ◽  
Stage Renal Disease

Peritoneal dialysis (PD) is a life-sustaining therapy for end-stage renal disease (ESRD), used by 10–15% of the dialysis population worldwide. Peritoneal fibrosis (PF) is a known complication of long-term PD and frequently follows episodes of peritonitis, rendering the peritoneal membrane inadequate for dialysis. Transforming growth factor (TGF)-β is an inducer of fibrosis in several tissues and organs, and its overexpression has been correlated with PF. Animal models of peritonitis have shown an increase in expression of TGF-β in the peritoneal tissue. Decorin, a proteoglycan and component of the extracellular matrix, inactivates TGF-β, consequently reducing fibrosis in many tissues. Recently, gold nanoparticles (GNP) have been used for drug delivery in a variety of settings. In the present study, we tested the possibility that GNP-delivered decorin gene therapy ameliorates zymosan-mediated PF. We created a PF model using zymosan-induced peritonitis. Rats were treated with no decorin, GNP-decorin, or adeno-associated virus-decorin (AAV-decorin) and compared with controls. Tissue samples were then stained for Masson's trichrome, enface silver, and hematoxylin and eosin, and immunohistochemistry was carried out with antibodies to TGF-β1, α-smooth muscle actin (α-SMA), and VEGF. Animals which were treated with GNP-decorin and AAV-decorin gene therapy had significant reductions in PF compared with untreated animals. Compared with untreated animals, the treated animals had better preserved peritoneal mesothelial cell size, a significant decrease in peritoneal thickness, and decreased α-SMA. Quantitative PCR measurements showed a significant decrease in the peritoneal tissue levels of α-SMA, TGF-β, and VEGF in treated vs. untreated animals. This study shows that both GNP-delivered and AAV-mediated decorin gene therapies significantly decrease PF in vivo in a rodent model. This approach has important clinical translational potential in providing a therapeutic strategy to prevent PF in PD patients.

scholarly journals The 37/67-Kilodalton Laminin Receptor Is a Receptor for Adeno-Associated Virus Serotypes 8, 2, 3, and 9

2006 ◽  
Vol 80 (19) ◽  
pp. 9831-9836 ◽  
Author(s):  
Bassel Akache ◽  
Dirk Grimm ◽  
Kusum Pandey ◽  
Stephen R. Yant ◽  
Hui Xu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cultured Cells ◽  
Human Gene ◽  
Laminin Receptor ◽  
Transduction Efficiency ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Tumor Gene

ABSTRACT Adeno-associated virus serotype 8 (AAV8) is currently emerging as a powerful gene transfer vector, owing to its capability to efficiently transduce many different tissues in vivo. While this is believed to be in part due to its ability to uncoat more readily than other AAV serotypes such as AAV2, understanding all the processes behind AAV8 transduction is important for its application and optimal use in human gene therapy. Here, we provide the first report of a cellular receptor for AAV8, the 37/67-kDa laminin receptor (LamR). We document binding of LamR to AAV8 capsid proteins and intact virions in vitro and demonstrate its contribution to AAV8 transduction of cultured cells and mouse liver in vivo. We also show that LamR plays a role in transduction by three other closely related serotypes (AAV2, -3, and -9). Sequence and deletion analysis allowed us to map LamR binding to two protein subdomains predicted to be exposed on the AAV capsid exterior. Use of LamR, which is constitutively expressed in many clinically relevant tissues and is overexpressed in numerous cancers, provides a molecular explanation for AAV8's broad tissue tropism. Along with its robust transduction efficiency, our findings support the continued development of AAV8-based vectors for clinical applications in humans, especially for tumor gene therapy.

scholarly journals Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens

2016 ◽  
Vol 90 (16) ◽  
pp. 7019-7031 ◽  
Author(s):  
Sarah C. Nicolson ◽  
Chengwen Li ◽  
Matthew L. Hirsch ◽  
Vincent Setola ◽  
R. Jude Samulski
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
High Throughput ◽  
Adeno Associated Virus ◽  
Virus Gene ◽  
Diploid Cells ◽  
High Throughput Screens ◽  
Group 1

ABSTRACTWhile the recent success of adeno-associated virus (AAV)-mediated gene therapy in clinical trials is promising, challenges still face the widespread applicability of recombinant AAV(rAAV). A major goal is to enhance the transduction efficiency of vectors in order to achieve therapeutic levels of gene expression at a vector dose that is below the immunological response threshold. In an attempt to identify novel compounds that enhance rAAV transduction, we performed two high-throughput screens comprising 2,396 compounds. We identified 13 compounds that were capable of enhancing transduction, of which 12 demonstrated vector-specific effects and 1 could also enhance vector-independent transgene expression. Many of these compounds had similar properties and could be categorized into five groups: epipodophyllotoxins (group 1), inducers of DNA damage (group 2), effectors of epigenetic modification (group 3), anthracyclines (group 4), and proteasome inhibitors (group 5). We optimized dosing for the identified compounds in several immortalized human cell lines as well as normal diploid cells. We found that the group 1 epipodophyllotoxins (teniposide and etoposide) consistently produced the greatest transduction enhancement. We also explored transduction enhancement among single-stranded, self-complementary, and fragment vectors and found that the compounds could impact fragmented rAAV2 transduction to an even greater extent than single-stranded vectors.In vivoanalysis of rAAV2 and all of the clinically relevant compounds revealed that, consistent with ourin vitroresults, teniposide exhibited the greatest level of transduction enhancement. Finally, we explored the capability of teniposide to enhance transduction of fragment vectorsin vivousing an AAV8 capsid that is known to exhibit robust liver tropism. Consistent with ourin vitroresults, teniposide coadministration greatly enhanced fragmented rAAV8 transduction at 48 h and 8 days. This study provides a foundation based on the rAAV small-molecule screen methodology, which is ideally used for more-diverse libraries of compounds that can be tested for potentiating rAAV transduction.IMPORTANCEThis study seeks to enhance the capability of adeno-associated viral vectors for therapeutic gene delivery applicable to the treatment of diverse diseases. To do this, a comprehensive panel of FDA-approved drugs were tested in human cells and in animal models to determine if they increased adeno-associated virus gene delivery. The results demonstrate that particular groups of drugs enhance adeno-associated virus gene delivery by unknown mechanisms. In particular, the enhancement of gene delivery was approximately 50 to 100 times better with than without teniposide, a compound that is also used as chemotherapy for cancer. Collectively, these results highlight the potential for FDA-approved drug enhancement of adeno-associated virus gene therapy, which could result in safe and effective treatments for diverse acquired or genetic diseases.

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