scholarly journals 993. Gene Delivery and Biodistribution in the Brain Following Adeno-Associated Virus Serotype 5 Vector-Mediated Gene Transfer

2007 ◽  
Vol 15 ◽  
pp. S379
Keyword(s):  
Gene Transfer ◽  
Gene Delivery ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Serotype 5 ◽  
The Brain

scholarly journals Supraspinal gene transfer by intrathecal adeno-associated virus serotype 5

2014 ◽  
Vol 8 ◽  
Author(s):  
Daniel J. Schuster ◽  
Lalitha R. Belur ◽  
Maureen S. Riedl ◽  
Stephen A. Schnell ◽  
Kelly M. Podetz-Pedersen ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Serotype 5

scholarly journals High-Resolution Structural Characterization of a New Adeno-associated Virus Serotype 5 Antibody Epitope toward Engineering Antibody-Resistant Recombinant Gene Delivery Vectors

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Ariana Jose ◽  
Mario Mietzsch ◽  
J. Kennon Smith ◽  
Justin Kurian ◽  
Paul Chipman ◽  
...  
Keyword(s):  
High Resolution ◽  
Gene Delivery ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
The United States ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Serotype 5 ◽  
Density Map

ABSTRACTAdeno-associated virus serotype 5 (AAV5) is being developed as a gene delivery vector for several diseases, including hemophilia and Huntington’s disease, and has a demonstrated efficient transduction in liver, lung, skeletal muscle, and the central nervous system. One limitation of AAV gene delivery is preexisting neutralizing antibodies, which present a significant challenge for vector effectiveness in therapeutic applications. Here, we report the cryo-electron microscopy (cryo-EM) and image-reconstructed structure of AAV5 in complex with a newly generated monoclonal antibody, HL2476, at 3.1-Å resolution. Unlike other available anti-AAV5 capsid antibodies, ADK5a and ADK5b, with epitopes surrounding the 5-fold channel of the capsid, HL2476 binds to the 3-fold protrusions. To elucidate the capsid-antibody interactions, the heavy and light chains were sequenced and their coordinates, along with the AAV5 viral protein, assigned to the density map. The high resolution of the complex enabled the identification of interacting residues at the 3-fold protrusions of the capsid, including R483, which forms two hydrogen bonds with the light chain of HL2476. A panel of AAV5 variants was generated and analyzed by native dot immunoblot and transduction assays. This identified variants with antibody escape phenotypes that maintain infectivity.IMPORTANCEBiologics based on recombinant AAVs (rAAVs) are increasingly becoming attractive human gene delivery vehicles, especially after the approval of Glybera in Europe and Luxturna in the United States. However, preexisting neutralizing antibodies against the AAV capsids in a large percentage of the human population limit wide-spread utilization of these vectors. To circumvent this problem, stealth vectors must be generated that are undetectable by these antibodies. This study details the high-resolution characterization of a new antigenic region on AAV5, a vector being developed for numerous delivery applications. The structure of AAV5 complexed with HL2476, a novel antibody, was determined by cryo-EM to 3.1-Å resolution. The resolution of the density map enabled the identification of interacting residues between capsid and antibody and the determinants of neutralization. Thus, the information obtained from this study can facilitate the generation of host immune escape vectors.

scholarly journals Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion

2018 ◽  
Vol 4 (11) ◽  
pp. eaau9859 ◽  
Author(s):  
Michael J. Castle ◽  
Yuhsiang Cheng ◽  
Aravind Asokan ◽  
Mark H. Tuszynski
Keyword(s):  
Gene Expression ◽  
Gene Delivery ◽  
Neurological Disorders ◽  
Fold Increase ◽  
Brain Regions ◽  
Intrathecal Administration ◽  
Simple Method ◽  
Virus Serotype ◽  
Cortical Regions ◽  
The Brain

Several neurological disorders may benefit from gene therapy. However, even when using the lead vector candidate for intrathecal administration, adeno-associated virus serotype 9 (AAV9), the strength and distribution of gene transfer to the brain are inconsistent. On the basis of preliminary observations that standard intrathecal AAV9 infusions predominantly drive reporter gene expression in brain regions where gravity might cause cerebrospinal fluid to settle, we tested the hypothesis that counteracting vector “settling” through animal positioning would enhance vector delivery to the brain. When rats are either inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, we find (i) a significant 15-fold increase in the number of transduced neurons, (ii) a marked increase in gene delivery to cortical regions, and (iii) superior animal-to-animal consistency of gene expression. Entorhinal, prefrontal, frontal, parietal, hippocampal, limbic, and basal forebrain neurons are extensively transduced: 95% of transduced cells are neurons, and greater than 70% are excitatory. These findings provide a novel and simple method for broad gene delivery to the cortex and are of substantial relevance to translational programs for neurological disorders, including Alzheimer’s disease and related dementias, stroke, and traumatic brain injury.

scholarly journals Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease

2003 ◽  
Vol 7 (5) ◽  
pp. 580-587 ◽  
Author(s):  
Reuben Matalon ◽  
Sankar Surendran ◽  
Peter L Rady ◽  
Michael J Quast ◽  
Gerald A Campbell ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Knockout Mouse ◽  
Canavan Disease ◽  
Adeno Associated Virus ◽  
The Brain

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.

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

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