An Emerging Adeno-Associated Viral Vector Pipeline for Cardiac Gene Therapy

Abstract

The naturally occurring adeno-associated virus (AAV) isolates display diverse tissue tropisms in different hosts. Robust cardiac transduction in particular has been reported for certain AAV strains. Successful applications of these AAV strains in preclinical and clinical settings with a focus on treating cardiovascular disease continue to be reported. At the same time, these studies have highlighted challenges such as cross-species variability in AAV tropism, transduction efficiency, and immunity. Continued progress in our understanding of AAV capsid structure and biology has provided the rationale for designing improved vectors that can possibly address these concerns. The current report provides an overview of cardiotropic AAV, existing gaps in our knowledge, and newly engineered AAV strains that are viable candidates for the cardiac gene therapy clinic.

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…Evidence of marked cardiac tropism for AAV9 in mice may represent a species-specific bias, however, as transduction profiles between small-and large-animal models vary. 67 Additionally, ubiquitous and tissuerestricted promoters used for systemic expression, such as desmin, CMV, or CBA, have a propensity to express in antigen presenting cells, resulting in deleterious innate and adaptive responses that eliminate transduced cells. [68][69][70][71] Therefore, inclusion of an immune tolerance-inducing construct may attenuate the immunogenicity of these vectors.…”

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

“…34,35 The performance of a given serotype greatly depends on the route of administration: whereas AAV1 and AAV6 seem more suitable for cardiac gene transfer through intramyocardial, intrapericardial, or intracoronary routes, AAV8 and AAV9 can also achieve efficient cardiac transduction when administered systemically. 36 Although the availability of these serotype variants has improved the relative efficiency of AAV vectors in specific, susceptible cell types, postmitotic cells still remain the preferential targets for these vectors in vivo. The molecular determinants of this peculiar tropism are still not completely clear.…”

“…Similarly, new AAV9 variants have been generated by random mutagenesis and selected for strong cardiac tropism and significantly less transgene expression in off-target by guest on http://circres.ahajournals.org/ Downloaded from organs (liver, kidney, pancreas). 36,170 Even better, AAV variants have been obtained by both AAV-based peptide display libraries 171 and DNA-shuffled libraries and direct evolution in mice (AAV2-PSVSPRP, AAV2-VNSTRLP, AAVM41). 172 Other AAV2-derived mutants, AAV2.15 and AAV2.4, contain mutations at critical antigenic sites and are thereby capable of evading neutralizing antibodies in human serum.…”

Copackaging of Multiple Adeno-Associated Viral Vectors in a Single Production Step

“…The widespread tropism, sustained gene expression, and excellent safety data that exist for AAV are only a few of the reasons it has reached such popularity. As a nonpathogenic shuttle for therapeutic genes, capable of delivering its payload to many cell types, the basic biological processes governing the behavior of the many AAV serotypes have been an extensive area of research for many years (Zincarelli et al, 2008;Asokan et al, 2012;Gurda et al, 2012;Aschauer et al, 2013;Asokan and Samulski, 2013;Rayaprolu et al, 2013). With its success in correcting the pathology associated with diseases such as seen in the multitude of metabolic myopathies and hematological disorders, AAV is quickly becoming the gene therapy vector of choice for initiating large animal studies and clinical trials (Markusic and Herzog, 2012;Mah et al, 2013).…”