scholarly journals Impact of capsid modifications by selected peptide ligands on recombinant adeno-associated virus serotype 2-mediated gene transduction

2012 ◽  
Vol 93 (10) ◽  
pp. 2131-2141 ◽  
Author(s):  
Matthias Naumer ◽  
Ruth Popa-Wagner ◽  
Jürgen A. Kleinschmidt
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Viral Vectors ◽  
Peptide Ligands ◽  
Gene Transduction ◽  
Cell Binding ◽  
Adeno Associated Virus ◽  
Vector Systems ◽  
Virus Serotype ◽  
Selection Of

Vectors based on adeno-associated virus serotype 2 (AAV2) belong to today’s most promising and most frequently used viral vectors in human gene therapy. Like in many other vector systems, the broad but non-specific tropism limits their use for certain cell types or tissues. One approach to screen for transduction-improved vectors is the selection of random peptide libraries displayed directly on the AAV2 capsid. Although the AAV2 library system has been widely applied for the successful selection of improved gene therapy vectors, it remains unknown which steps of the transduction process are most affected and therefore critical for the selection of targeting peptides. Attachment to the cell surface is the first essential step of AAV-mediated gene transduction; however, our experiments challenge the conventional belief that enhanced gene transfer is equivalent to more efficient cell binding of recombinant AAV2 vectors. A comparison of the various steps of gene transfer by vectors carrying a wild-type AAV2 capsid or displaying two exemplary peptide ligands selected from AAV2 random libraries on different human tumour cell lines demonstrated strong alterations in cell binding, cellular uptake, as well as intracellular processing of these vectors. Combined, our results suggest that entry and post-entry events are decisive for the selection of the peptides NDVRSAN and GPQGKNS rather than their cell binding efficiency.

Adeno-Associated Viral Vectors for Gene Transfer and Gene Therapy

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
H. Büeler
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Adeno Associated Virus ◽  
Viral Genes ◽  
Virus Recombinant

AbstractAdeno-associated virus (AAV) is a defective, non-pathogenic human parvovirus that depends for growth on coinfection with a helper adenovirus or herpes virus. Recombinant adeno-associated viruses (rAAVs) have attracted considerable interest as vectors for gene therapy. In contrast to other gene delivery systems, rAAVs lack all viral genes and show long-term gene expression

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Hemophilia gene therapy comes of age

2017 ◽  
Vol 1 (26) ◽  
pp. 2591-2599 ◽  
Author(s):  
Lindsey A. George
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Factor Ix ◽  
Large Animal Model ◽  
Large Animal ◽  
Adeno Associated Virus ◽  
Target Disease ◽  
American Society ◽  
Clinical Trial Results

Abstract Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first “cure” in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016. This progression to clinically meaningful success combined with numerous ongoing recombinant adeno-associated virus (rAAV)–mediated hemophilia gene transfer clinical trials suggest that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized. Although several novel therapeutics have recently emerged for hemophilia, gene therapy is unique in its potential for a one-time disease-altering, or even curative, treatment. This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.

scholarly journals Sterile Abscess in the Myocardium after Direct Intramyocardial Injection Related to Gene Therapy in a Swine Model

2011 ◽  
Vol 2011 ◽  
pp. 1-2 ◽  
Author(s):  
Kiyotake Ishikawa ◽  
Dennis Ladage ◽  
Lisa Tilemann ◽  
Yoshiaki Kawase ◽  
Roger J. Hajjar
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Viral Vectors ◽  
Swine Model ◽  
Clinical Settings ◽  
Intramyocardial Injection ◽  
New Therapy ◽  
Sterile Abscess ◽  
Efficient Gene ◽  
Cardiac Gene

Cardiac gene therapy is one of the most promising approaches to cure patients with cardiac dysfunctions. Many ways of efficient gene transfer using viral vectors are tested, and some of them are already used in clinical settings. However, it is always important to be keenly alert to the possible complications when a new therapy is introduced. We present a case of myocardial sterile abscess in a swine model associated with a direct myocardial injection.

scholarly journals Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Emilie Audouard ◽  
Valentin Oger ◽  
Béatrix Meha ◽  
Nathalie Cartier ◽  
Caroline Sevin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Metachromatic Leukodystrophy ◽  
Early Death ◽  
Lysosomal Storage ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Brain And Spinal Cord ◽  
Sulfatide Accumulation

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.

Abstract 321: Cardiac Function Improvement Following In vivo Intracoronary Adeno-Associated Virus Type 1 Vector Gene Transfer of SERCA2a in a Pre-Clinical Model of Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hung Q Ly ◽  
Yoshiaki Kawase ◽  
Fabrice A Prunier ◽  
Djamel Lebeche ◽  
Yafen Shi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Adeno Associated Virus ◽  
Inotropic Effects ◽  
Clinical Model ◽  
Virus Serotype

Background: Reduced activity and expression of sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) is known to occur in HF. Method: Our 4-month study examined the effects of SERCA2a gene transfer in a swine volume-overload HF (VO-HF) model. Using Yorkshire-Landrace swine, HF was created by severing mitral apparatus chordae to induce mitral regurgitation. Results: At 2 months (M), a compensated state of VO-HF was found: prolongation of the rate of isovolumic relaxation (Tau), increased left ventricular internal diameter diastolic and systolic diameters (LVIDd, LVIDs). At 2M, intracoronary injection of adeno-associated virus serotype 1 vector carrying SERCA2a under a cytomegalovirus promoter (AAV1.SERCA2a) (n = 10) vs. saline (n = 6) was performed. At 4M, gene transfer resulted in (A) positive LV inotropic effects: (dP/dt)/P, 15.5 ± 3.0 sec − 1 SERCA2a-group vs. 21.2 ± 3.2 sec − 1 controls; p < 0.01; (B) a favorable trend in LV lusitropic effects: Tau, 0.037 ± 0.019 vs. 0.051 ± 0.01 msec, p = 0.09; (C) improvement in LV geometry: % change in LVIDs, +15 ± 11% controls vs. −3.0 ± 10% SERCA2a-group, p < 0.01. At 4M, BNP levels remained stable in post- SERCA2a gene transfer, in contrast to the progressive rising levels among controls. Further, cardiac SERCA2a expression was significantly decreased in controls whereas it was restored to normal levels in the SERCA2a group (Figure ). Lastly, there was no histopathological evidence of myocardial inflammatory reaction or necrosis. Conclusion: Overexpression of SERCA2a by in vivo AAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction and improved ventricular remodeling.

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.

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