Improving clinical efficacy of adeno associated vectors by rational capsid bioengineering.

Dwaipayan Sen

doi:10.1186/s12929-014-0103-1

Abstract

Adeno associated vectors (AAV) have shown considerable promise to treat various genetic disorders in both preclinical and clinical settings mainly because of its safety profile. However, efficient use of AAV to deliver genes in immune-competent sites like muscles and liver requires very high doses which are associated with concomitant cellular immune response against the viral capsids leading to destruction of the transduced cells. Coupled with that, there are enough evidences that at high doses, AAV particles are subjected to increased cellular phosphorylation/uniquitination leading to proteasome mediated degradation and loss of the viral particles. The presence of preexisting immunity against AAV further adds on to the problem which is acting as a major roadblock to efficiently use it as a gene therapy vector in the clinics. To overcome this, rational bioengineering of AAV capsid becomes a prime tool by which specific amino acid residue(s) can be suitably modified/replaced by compatible residue(s) to create vectors having lower host immune response and higher intracellular trafficking rate. This article reviews the various aspects of rationally designing AAV capsids like by site-directed mutagenesis, directed evolution and combinatorial libraries which can create vectors having not only immune evasive property but also enhanced gene expression and transduction capability. One or more combinations of these strategies have strong potential to create novel vectors which will have suitable clinical efficiency even at a low dose.

Highlights

associated vectors (AAV) Biology Adeno-associated virus (AAV) is a non-pathogenic parvovirus that has been widely used as a vector of choice for gene therapy
The residues chosen for mutation were selected based on structural predictions on their presence in and around phosphodegrons on the AAV capsid structure as well as residues which lie in the antigenic epitopes that will create vectors which will be efficient in terms of higher transduction and gene expression, and will have reduced neutralizing antibody response against the viral capsids allowing for persistent transgene expression
AAV has gained immense popularity as a gene therapy vehicle to treat several genetic disorders, there is still a persistent need to further improve on the vector capsid design and engineering which can bypass the problem of neutralization by preexisting antibodies as well as T-cell mediated immune clearance

Summary

Introduction

AAV Biology Adeno-associated virus (AAV) is a non-pathogenic parvovirus that has been widely used as a vector of choice for gene therapy. For example in the first clinical trial for hemophilia B conducted by Katherine High’s group [11] there was strong-cell mediated immune response against the AAV capsid antigens in the high dose recipient subject which lead to destruction of the AAV2 transduced hepatocytes resulting in only transient therapeutic expression of Factor (F).

Results

Conclusion