AAV for Gene Therapy

The utilisation of adeno-associated viruses (AAV) has revolutionised the practice of viral vectors for gene therapy and transgenic expression due to its significant advantages as a gene delivery system. Simply put, AAV is a protein shell that surrounds a small DNA genome of around 4.7kb in length [1].

There are also methods of enhancing the expression of a gene, namely cis-regulatory elements, for example, WPRE (Woodchuck Posttranscriptional Regulatory Element) and Poly A are often found in transfer plasmids, just up from the final ITR. WPRE helps transcribed RNA form a tertiary structure, as well as assisting nuclear export to the cytoplasm [3-4]. Similarly, Poly A aids export to the cytoplasm, this process is critical as can be seen in the ‘AAV Entering Host Cell’ diagram in stages 3 to 4 . If the RNA is not extracted to the cytoplasm, then the desired protein will not be synthesized, thus treatment will be unsuccessful. It additionally stabilises RNA by protecting it from degradation and aids RNA translation, both of these assist expressions of the desired gene [5-6]. Additional information on cis-regulatory elements Poly A and WPRE can be found in the list of references at the bottom of the webpage.

One vital characteristic of AAV that makes it considerably more advantageous than more traditional methods is its lack of pathogenicity. Pathogenicity itself can be defined by how much damage can be caused to host cells, and since AAVs cause negligible harm, it makes it an ideal vector. This, in turn, means that unwell patients with heavily occupied immune systems may still be able to undergo gene therapy, thus reducing the impact of symptoms.

Another advantage of AAV is that it has the potential to affect both dividing and quiescent (non-dividing) meaning it impacts a wide range of cells. In addition to this, AAVs often result in long-term expression in quiescent cells as the viral DNA isn’t diluted until the cell proliferates [7].

There are multiple different strains of AAV, currently, a total of 12 have been discovered, all with very little current research or application. These variants can be manipulated in vivo to create custom vectors as well as custom-designed AAV capsids. Although, AAV 2 currently is the most studied and utilised in gene therapy due to its tropism to the most commonly desired cells. It has also proven dependable in cases of ovarian cancer treatments without any effect on healthy host cells [8].
 

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