AAV Gene Therapy

biogene123 authored almost 2 years ago

Adeno-associated virus (AAV) is a small, non-enveloped virus that was adapted as a gene transfer vector 30 years ago. It is capable of transducing a variety of species and tissues in vivo without evidence of toxicity, and it produces a relatively mild innate and adaptive immune response. We will analyze the basic biology of AAV, the development history of AAV vector technology, and some clinical and research applications of AAV's success, as well as the considerations mentioned by researchers.

Adeno-associated virus belongs to the family Parvoviridae, is a non-enveloped single-stranded (positive or negative) linear DNA-deficient virus. It is the smallest virus among animal viruses. AAV cannot exist on its own. In the presence of helper viruses such as adenovirus and herpes simplex virus, AAV can replicate and synthesize assembly proteins in infected host cells to produce new virus particles.

The main cell entry mechanism of AAV is endocytosis through the use of clathrin-coated pits. Although other secondary mechanisms may also be involved in this process. However, these alternative secondary mechanisms have not been proven. When AAV binds to its cell surface receptors, it stimulates intracellular signaling pathways, which in turn stimulates the internalization of AAV.

Gene therapy is a new method for treating a range of hereditary and non-hereditary diseases by delivering therapeutic genes to specific organs or tissues. Among the viral vectors that have been used to deliver the gene of interest to date, the adeno-associated virus (AAV) vector appears to be the safest and most effective vector and has the ability to maintain long-term gene and protein expression after infection. Gene therapy research using the AAV vector has shown significant progress not only in animal models but also in human gene therapy that is not yet pathogenic.

Pseudotyping, discovery of new strategies for recombining AAV structure into other serotype capsids, and the development of scAAV vectors that can effectively change tissue tropism and increase transduction efficiency has opened up new ways to produce more attractive vectors for clinical applications including hemophilia B, Parkinson's disease and rheumatoid arthritis.

AAV virus protein has been shown to cause minimal immunogenic response, and at the same time, it can produce extended expression of treatment-related genes/proteins. In addition, AAV has a reduced pro-inflammatory risk compared to other potential viral vectors, such as lentiviral vectors, and is considered to be one of the most promising gene transfer vectors for in vivo gene therapy. However, it has been reported that in some experimental settings, the immune response generated by AAV administration appears to impair the effectiveness of AAV-mediated gene therapy. Therefore, there are several factors that can determine the immune response to AAV-based proteins, including administration, dosage, serotype, host species, the occurrence of transgenic and expression cassette routes, and pre-existing immune AAV.

Many studies have explored the therapeutic potential of these engineered AAV vectors for many diseases. After decades of experimental research, in 2012, the European Commission (EU) approved the first successful human gene therapy protocol using the AAV serotype 1 vector for the treatment of lipoprotein lipase deficiency (LPLD), an extremely rare genetic disease. In recent years, the most common clinical trial of AAV-based therapy has been in hemophilia B. In addition, many advances have been made in identifying mechanisms involved in chronic organ injury, which opens the way for gene therapy research. Despite extensive preclinical and clinical research over the past few decades, gene therapies have been developed for hereditary diseases. Although some preclinical studies have been performed in animal models, only a few clinical trials have been used to study the effect of gene therapy on hereditary diseases.

Successful gene therapy methods should achieve long-term gene expression while delivering an appropriate amount of the therapeutic gene to the target tissue without significant toxicity. Among all currently available viral vectors, including retroviruses, lentiviruses, adenoviruses and AAV vectors, AAV is a unique non-pathogenic viral vector with a wide range of tissue tropism and has the potential to become the leading vector for gene therapy research in future. Unlike recombinant adenoviral vectors that produce high initial gene expression and are rapidly reduced due to immune clearance, AAV vector-based gene expression is persistent. In addition, AAV vectors mediate the smallest cell-mediated immune response, which is advantageous for persistent gene transduction into host cells. However, compared to other viral vectors, a significant disadvantage associated with AAV is its small package size, which limits the size of transgenes delivered using this vector. New molecular engineering methods have the potential to overcome these limitations. Therefore, genetically engineered AAV is expected to become the main carrier of human gene therapy.

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