Adeno-associated Virus as a Gene Therapy Vector: Vector Development, Production and Clinical Applications

2005 ◽  
pp. 119-145 ◽  
Author(s):  
Joshua C. Grieger ◽  
Richard J. Samulski
Keyword(s):  
Gene Therapy ◽  
Clinical Applications ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector

Adeno-associated virus as a gene therapy vector: strategies to neutralize the neutralizing antibodies

2019 ◽  
Vol 19 (3) ◽  
pp. 289-298 ◽  
Author(s):  
Majid Lotfinia ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Behzad Hatami ◽  
Mohammad Reza Zali ◽  
Morteza Karimipoor
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector

scholarly journals Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector

2021 ◽  
Vol 20 ◽  
pp. 95-108
Author(s):  
Agostina Carestia ◽  
Seok-Joo Kim ◽  
Franziska Horling ◽  
Hanspeter Rottensteiner ◽  
Christian Lubich ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Microenvironment ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Virus Serotype

scholarly journals Adeno-associated Virus Receptor-binding: Flexible Domains and Alternative Conformations through cryo-Electron Tomography of AAV2 and AAV5 complexes

2022 ◽  
Author(s):  
Guiqing Hu ◽  
Mark A Silveria ◽  
Michael S Chapman ◽  
Scott M Stagg
Keyword(s):  
Electron Microscopy ◽  
Gene Therapy ◽  
Viral Entry ◽  
Electron Tomography ◽  
Particle Analysis ◽  
Fold Axis ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Molecular Virology ◽  
Cryo Electron Tomography

Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV's molecular virology is needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near universal entry receptor, AAVR, and structures by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N-termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors. IMPORTANCE: With 150 clinical trials for 30 diseases underway, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction, has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains.

Combinatorial engineering of a gene therapy vector: directed evolution of adeno-associated virus

2006 ◽  
Vol 8 (2) ◽  
pp. 155-162 ◽  
Author(s):  
Luca Perabo ◽  
Jan Endell ◽  
Susan King ◽  
Kerstin Lux ◽  
Daniela Goldnau ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Directed Evolution ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Combinatorial Engineering

scholarly journals Cross-species permissivity: structure of a goat adeno-associated virus and its complex with the human receptor, AAVR

2022 ◽  
Author(s):  
Edward E Large ◽  
Mark A Silveria ◽  
Tommi A White ◽  
Michael S Chapman
Keyword(s):  
Gene Therapy ◽  
Conformational Changes ◽  
Cell Entry ◽  
Adeno Associated Virus ◽  
Virus Structure ◽  
Gene Therapy Vector ◽  
Binding Interface ◽  
Atomic Interactions ◽  
Entry Receptor ◽  
Protein Shell

Adeno-associated virus (AAV) is a small ssDNA satellite virus of high interest (in recombinant form) as a safe and effective gene therapy vector. AAV's human cell entry receptor (AAVR) contains Polycystic Kidney Disease (PKD) domains bound by AAV. Seeking understanding of the spectrum of interactions, goat AAVGo.1 is investigated, because its host is the species most distant from human with reciprocal cross-species cell susceptibility. The structure of AAVGo.1, solved by cryo-EM to 2.9 Å resolution, is most similar to AAV5. Through ELISA studies, it is shown that AAVGo.1 binds to human AAVR (huAAVR) more strongly than do AAV2 or AAV5, and that it joins AAV5 in a class that binds exclusively to PKD domain 1 (PKD1), in contrast to other AAVs that interact primarily with PKD2. The AAVGo.1 cryo-EM structure of a complex with a PKD12 fragment of huAAVR at 2.4 Å resolution shows PKD1 bound with minimal change in virus structure, except for disordering of a neighboring surface loop. Only 4 of the 42 capsid protein sequence differences between AAVGo.1 and AAV5 occur at the PKD1 binding interface. These result in only minor conformational changes in AAVR, including a near rigid domain rotation with maximal displacement of the receptor by ~1 Å. A picture emerges of two classes of AAV with completely different modes of binding to the same AAVR receptor, but within each class atomic interactions are mostly conserved. IMPORTANCE Adeno-Associated Virus (AAV) is a small ssDNA satellite parvovirus. As a recombinant vector with a protein shell encapsidating a transgene, recombinant AAV (rAAV) is a leading delivery vehicle for gene therapy with two FDA-approved treatments and 150 clinical trials for 30 diseases. The human entry receptor huAAVR has five PKD domains. To date, all serotypes, except AAV5, have interacted primarily with the second PKD domain, PKD2. Goat is the AAV host most distant from human with cross-species cell infectivity. AAVGo.1 is similar in structure to AAV5, the two forming a class with a distinct mode of receptor-binding. Within the two classes, binding interactions are mostly conserved, giving an indication of the latitude available in modulating delivery vectors.

Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma

2014 ◽  
Vol 5 (9) ◽  
pp. 975-990
Author(s):  
Paladd Asavarut ◽  
Kevin O'Neill ◽  
Nelofer Syed ◽  
Amin Hajitou
Keyword(s):  
Gene Therapy ◽  
Malignant Glioma ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Targeted Gene Therapy
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