Rational design of smart supramolecular assemblies for gene delivery: chemical challenges in the creation of artificial viruses

2012 ◽  
Vol 41 (7) ◽  
pp. 2562-2574 ◽  
Author(s):  
Kanjiro Miyata ◽  
Nobuhiro Nishiyama ◽  
Kazunori Kataoka
Keyword(s):  
Gene Delivery ◽  
Rational Design ◽  
Supramolecular Assemblies ◽  
The Creation

Legalization in context: The design of the WTO’s dispute settlement system

2017 ◽  
Vol 19 (2) ◽  
pp. 304-319 ◽  
Author(s):  
Manfred Elsig
Keyword(s):  
Rational Design ◽  
Dispute Settlement ◽  
The United States ◽  
Settlement System ◽  
Trading System ◽  
Wto Dispute Settlement ◽  
Multilateral Trading System ◽  
The Creation ◽  
Dispute Settlement System

This article asks why the dispute settlement provisions of the multilateral trading system underwent significant reforms during the negotiations that led to the creation of the World Trade Organization (WTO) in 1995. Why did the leading trading powers accept a highly legalized system that departed from established political–diplomatic forms of settling disputes? The contribution of this article is threefold. First, it complements existing accounts that exclusively focus on the United States with a novel explanation that takes account of contextual factors. Second, it offers an in-depth empirical case study based on interviews with negotiators who were involved and novel archival evidence on the creation of the new WTO dispute settlement system. Third, by unpacking the long-standing puzzle of why states designed a highly legalized system, it addresses selected blind spots of the legalization and the rational design literatures with the aim of providing a better understanding about potential paths leading toward significant changes in legalization.

Molecular Printboards: Versatile Platforms for the Creation and Positioning of Supramolecular Assemblies and Materials

ChemInform ◽  
2007 ◽  
Vol 38 (8) ◽  
Author(s):  
Manon J. W. Ludden ◽  
David N. Reinhoudt ◽  
Jurriaan Huskens
Keyword(s):  
Supramolecular Assemblies ◽  
The Creation

Structurally Mapping Antigenic Epitopes of Adeno-Associated Virus 9: Development of Antibody Escape Variants

2021 ◽  
Author(s):  
Shanan N. Emmanuel ◽  
J. Kennon Smith ◽  
Jane Hsi ◽  
Yu-Shan Tseng ◽  
Matias Kaplan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibodies ◽  
Gene Delivery ◽  
General Population ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Transduction Efficiency ◽  
Viral Neutralization ◽  
Patient Cohort ◽  
Antigenic Epitopes

Adeno-associated viruses (AAV) serve as vectors for therapeutic gene delivery. AAV9 vectors have been FDA approved, as Zolgensma®, for the treatment of spinal muscular atrophy and is being evaluated in clinical trials for the treatment of neurotropic and musculotropic diseases. A major hurdle for AAV-mediated gene delivery is the presence of pre-existing neutralizing antibodies in 40 to 80% of the general population. These pre-existing antibodies can reduce therapeutic efficacy through viral neutralization, and the size of the patient cohort eligible for treatment. In this study, cryo-electron microscopy and image reconstruction was used to define the epitopes of five anti-AAV9 monoclonal antibodies (MAbs); ADK9, HL2368, HL2370, HL2372, and HL2374, on the capsid surface. Three of these, ADK9, HL2370, and HL2374, bound on or near the icosahedral 3-fold axes, HL2368 to the 2/5-fold wall, and HL2372 to the region surrounding the 5-fold axes. Pseudo-atomic modeling enabled the mapping and identification of antibody contact amino acids on the capsid, including S454 and P659. These epitopes overlap with previously defined parvovirus antigenic sites. Capsid amino acids critical for the interactions were confirmed by mutagenesis followed by biochemical assays testing recombinant AAV9 (rAAV9) variants capable of escaping recognition and neutralization by the parental MAbs. These variants retained parental tropism and had similar or improved transduction efficiency compared to AAV9. These engineered rAAV9 variants could expand the patient cohort eligible for AAV9-mediated gene delivery by avoiding pre-existing circulating neutralizing antibodies. IMPORTANCE The use of recombinant AAVs (rAAVs) as delivery vectors for therapeutic genes is becoming increasingly popular, especially following the FDA approval of Luxturna® and Zolgensma®, based on serotypes AAV2 and AAV9, respectively. However, high titer anti-AAV neutralizing antibodies in the general population, exempts patients from treatment. The goal of this study is to circumvent this issue by creating AAV variant vectors not recognized by pre-existing neutralizing antibodies. The mapping of the antigenic epitopes of five different monoclonal antibodies (MAbs) on AAV9, to recapitulate a polyclonal response, enabled the rational design of escape variants with minimal disruption to cell tropism and gene expression. This study, which included four newly developed and now commercially available MAbs, provides a platform for the engineering of rAAV9 vectors that can be used to deliver genes to patients with pre-exiting AAV antibodies.

Rational design of cationic cyclooligosaccharides as efficient gene delivery systems

2008 ◽  
pp. 2001 ◽  
Author(s):  
Alejandro Díaz-Moscoso ◽  
Patricia Balbuena ◽  
Marta Gómez-García ◽  
Carmen Ortiz Mellet ◽  
Juan M. Benito ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Rational Design ◽  
Delivery Systems ◽  
Efficient Gene

scholarly journals A Kinetic Model of Oligonucleotide–Brush Interactions for the Rational Design of Gene Delivery Vectors

2019 ◽  
Vol 20 (6) ◽  
pp. 2218-2229 ◽  
Author(s):  
Fengjin Qu ◽  
Danyang Li ◽  
Xiaoyan Ma ◽  
Fang Chen ◽  
Julien E. Gautrot
Keyword(s):  
Gene Delivery ◽  
Kinetic Model ◽  
Rational Design ◽  
Gene Delivery Vectors

scholarly journals Supramolecular Assemblies of Peptides or Nucleopeptides for Gene Delivery

Theranostics ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 3213-3222 ◽  
Author(s):  
Huaimin Wang ◽  
Zhaoqianqi Feng ◽  
Bing Xu
Keyword(s):  
Gene Delivery ◽  
Supramolecular Assemblies
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