Virus! Hearing this, it's not unusual to think of tragedy, fever, pain, pandemic, among many other negative connotations. Every day we are exposed to viral particles that can have lethal effects on us and on our loved ones, which explains the frequent conversation about "viruses" in scientific congresses.
Nonetheless, a virus today could save your life. Yes, you read that right. The study of its various morphologies and variety of genomes has allowed for the manipulation of these very elements to use them in our favor in delicate treatments. Among them, it's worth highlighting their use in extraordinary gene therapy, where viral vectors can be implemented to induce genetic modifications: just as the delivery person arrives at your house with "delivery," the virus can deliver to your cells the gene they need to cure your illness.
Adeno-associated viral (AAV) vectors are among the most used in this endeavor. The global market size for the manufacturing of adeno-associated virus vectors was valued at USD 767.7 million in 2022 and is projected to expand at a compound annual growth rate of 22.5% from 2023 to 2030. These tiny viruses from the parvovirus family owe their name to their lack of autonomy, as they need adenoviruses to replicate. Although AAVs have not been associated with diseases, adenoviruses are indeed harmful, and their contribution is essential for AAV replication. This is where science fiction becomes reality: instead of relying on a pathogenic virus, the adenovirus is replaced with a helper plasmid, designed to provide the necessary viral proteins for replication. This way, there would be no dependency on the adenovirus, thanks to the use of the constructed plasmid.
This replacement has been greatly beneficial as it allows the use of AAVs to treat diseases at the genetic level, through injections where corrected or completely new genes are introduced. These applications include treatments for diseases associated with the central nervous system, Stargardt's disease, muscular dystrophies, hemophilia A and B, various heart diseases, among others. It's worth noting that in the past year, it has been used for advances in the cure of HSV-1 (the strain of the virus that causes herpes).
As useful as it is, the manufacturing of the plasmid is complex, costly, and requires high precision. It must provide proteins that 1) cooperate to initiate transcription and modulate it within the host cell, 2) facilitate DNA synthesis, and 3) finally, inhibit protective functions and block antiviral responses.
The authors of a paper recently published in the journal Human Gene Therapy did not want to discard the potential of AAVs. In that paper, titled “An improved helper plasmid containing deletions in the E4 and E2a genes results in increased productivity of adeno-associated virus,” they explain that they managed to obtain a smaller, easier-to-manufacture plasmid that also produced twice as many AAVs, based on deletions in its genetic material. Both modified genes are associated with the three functions mentioned, as they stabilize single-stranded DNA during replication, inhibit the DNA damage response, and facilitate the export of viral RNA from the nucleus to the cytoplasm. This manipulation of its genome allowed for the preservation of essential functions, while increasing efficiency and yield in the proliferation of viral particles.
The development of viral vectors like AAVs, along with advances like the optimization of helper plasmids, highlights how science has been able to transform these natural threats into powerful tools for curing previously untreatable diseases. The paper mentioned in this article represents a small fraction of many more examples that justify the high potential of using viruses in gene treatments. Although viruses may manifest as unsafe entities and generate uncertainty, the possibilities for manipulation and their applications are vast and promising, opening a new horizon in modern medicine and redefining what a virus means in the context of life and death.
Author: Jazmin Agosti
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