Adeno-Associated Virus (AAV): A Promising Gene Therapy Delivery Vector

The realm of contemporary medicine has been invigorated by the captivating prospects presented by gene therapy, heralding possibilities in the treatment of various genetic and chronic afflictions. At the forefront of this transformative landscape, the Adeno-associated virus (AAV) has emerged as a focal point of extensive research and application in the sphere of gene therapy, igniting a beacon of hope for numerous patient communities.

What is AAV?

AAV is a class of diminutive viruses characterized by their minute viral particle dimensions, spanning a remarkable diameter ranging from 20 to 26 nanometers. Diverging from other viruses, AAV assumes the role of a replication-deficient entity, relying on the aid of other viruses, such as adenoviruses or herpesviruses, to facilitate its replication and amplification processes within the intricate milieu of host cells. The genome of AAV is embodied by a single-stranded DNA molecule, encompassing a versatile range in size, spanning from 4.7 to 6 kilobase pairs. This unique genomic propels AAV into the vanguard of gene delivery vectors, boasting an exceptional potential for targeted and efficient genetic transportation.

Fig.1 AAV life cycle (Daya S., Berns K. I. 2008).

AAV as a Gene Therapy Delivery Vector

Navigating the intricate landscape of gene therapy demands an astute selection of a delivery vector that can effectively ferry therapeutic genes into the targeted cells of patients. In this context, Adeno-Associated Virus (AAV) has emerged as a focal point within the realm of gene therapy delivery platforms, owing to a plethora of distinctive characteristics that underscore its pivotal role. Here are some key advantages of AAV as a gene therapy delivery vector:

1. High Safety Profile

AAV's pervasive presence in nature, with an astounding exposure rate of nearly 8 out of every 10 individuals over the course of their lifetimes, underscores its innate safety. Notably, the absence of any reported instances of AAV inciting illness in human subjects solidifies its standing as a vector of remarkable safety assurance.

2. Low Immunogenicity

In certain gene therapy applications, the unwelcome emergence of immune responses poses a significant challenge. However, AAV's strategic infiltration into tissues at amplified local concentrations, such as muscular, cerebral, or ocular tissues, often evades prompt clearance by the immune system. This inherent ability lends AAV an advantageous position marked by relatively subdued immunogenicity.

3. Broad Tropism

AAV's unparalleled ability to infiltrate a diverse array of cells, irrespective of their divisional status, sets the stage for its widespread application across an expansive spectrum of cell types. Notably, this distinctive attribute facilitates AAV's seamless integration into both quiescent and actively dividing cell populations, further amplifying its versatility.

4. Prolonged Expression

Within the intricate confines of host cells, recombinant AAV (rAAV) assumes the form of episomes ensconced within the cellular nucleus, orchestrating a protracted span of gene expression that can extend beyond the five-month milestone, particularly within slowly proliferating tissues. This enduring expression capability consolidates AAV's significance in sustaining long-term therapeutic outcomes.

5. Strong Spreadability

Notably eclipsing the spreadability benchmarks set by adenoviruses and lentiviruses, rAAV exhibits a robust dissemination prowess, transcending conventional barriers, including the formidable blood-brain barrier. This unparalleled ability designates AAV as promising for pioneering advancements in gene therapy, particularly within the intricacies of the nervous system.

6. High Stability

The exceptional resilience of rAAV viruses, capable of withstanding extended periods of storage at temperatures spanning the range of 2-8°C, streamlines the logistical management of these vectors during the phases of preparation and distribution. This pronounced stability characteristic amplifies AAV's practical utility, rendering it an important tool within the spectrum of gene therapy applications.

Progress in AAV Research

AAV was first discovered in laboratory adenovirus preparations in 1965. Over the subsequent decade, scientists primarily focused their research on aspects such as the genetic structure and composition of AAV, DNA replication and transcription, the latent nature of infection, and the assembly of viral particles. In 1982, they successfully cloned and sequenced the genome of AAV2, unveiling the mysteries surrounding AAV. These early studies provided a solid theoretical foundation for the widespread use of AAV as a gene delivery vector.

AAV vectors were first used for the treatment of cystic fibrosis in humans in 1995. In the 21st century, an increasing number of AAV serotype families were discovered, greatly enriching the toolbox of AAV vectors for in vivo gene delivery. In 2008, AAV-based gene therapy demonstrated compelling evidence of its efficacy in treating Leber's congenital amaurosis. In 2012, the first AAV-based gene therapy drug, Glybera, received approval from the European Medicines Agency (EMA), and five years later, Luxturna became the first AAV gene therapy product approved by the U.S. Food and Drug Administration (FDA) for treating genetic retinal diseases caused by RPE65 gene mutations.

Applications of AAV in Gene Therapy

In the ever-evolving landscape of gene therapy, the AAV stands tall as a formidable vector, showcasing its potential across various disease domains. Its utility has surfaced prominently in the following areas:

1. Treatment of Retinal Diseases

Within the domain of gene therapy, AAV emerges as a guiding light, illuminating the path toward combating an array of retinal diseases. Notably, it has shown promising prospects in tackling the intricate nuances entwined with the enigmatic RPE65 gene and its intricate web of complexities.

2. Treatment of Hematological Diseases

Unveiling its potential within the intricate fabric of hematological ailments, AAV unfurls a tapestry of possibilities, captivating a cohort of researchers ardently pioneering innovative methodologies. Leveraging the inherent potential of AAV as a precision vehicle for gene delivery to extend life to humans grappling with a spectrum of rare genetic blood disorders, encompassing the intricate dimensions of afflictions such as hemophilia and thalassemia.

3. Treatment of Neurological Disorders

Bolstered by its robust diffusion dynamics and its ability to sustain long-term stable expression, AAV emerges as a potent force in the realm of combating neurological disorders. Diving into uncharted territories, several studies are delving into the potential of AAV as a conduit for delivering therapeutic genes, with a keen focus on unraveling the complexities of conditions like Parkinson's disease, Huntington's disease, and an array of genetic neuromuscular afflictions.

Adeno-associated virus (AAV), as a gene therapy delivery vector, demonstrates boundless potential. Its advantages ranging from its impeccable safety profile and minimal immunogenicity to its expansive infectivity spectrum and enduring stable expression, have rendered it a hot of research in the field of gene therapy.

References

1. Wang D.; et al. Adeno-associated virus vector as a platform for gene therapy delivery. Nature Reviews Drug discovery. 2019, 18(5): 358-378.
2. Daya S.; Berns K. I. Gene therapy using adeno-associated virus vectors. Clinical Microbiology Reviews. 2008, 21(4): 583-593.