Adenoviruses in Gene Therapy & Gene Editing

(Posted on Monday, July 1, 2024)

One of the more exciting opportunities in medical technology is using a virus to carry genetic information in the form of DNA and RNA in the cells. One of the most commonly used viruses is adenoviruses. In fact, adenoviruses account for about 15% of all such efforts. Here, we will explain what an adenovirus is and how it can be used for gene therapy.

How Adenoviruses Are Used in Gene Therapy

Adenoviruses are able to carry therapeutic genes into target cells. 

The vector connects to specific receptors on the surface of target cells, allowing the adenovirus to enter the cell. After that, the adenovirus goes to the nucleus and introduces its genetic material, a double-stranded DNA molecule. This molecule is sometimes found in strand form and in more modern adenoviral vectors in circular form. This DNA doesn’t become part of the cell’s genetic material but stays separate. This mechanism is called episomal gene expression. The viral DNA can start the process of gene expression, called transduction, to encode the therapeutic protein by the inserted gene. These vectors can also be used to carry RNAs or CRISPR into cells.

Adenoviruses can carry their payloads into both dividing and non-dividing cells. The separate viral genetic material isn’t copied during cell division in dividing cells, so gene expression is only temporary. However, the separate viral genetic material can stay long in non-dividing cells like neurons or muscle cells, allowing continuous therapeutic gene expression. This makes gene replacement therapy possible for genetic disorders affecting these cell types.

Diversity of Adenoviruses

Adenoviruses are a large family of viruses, with over 100 types identified. They infect many hosts, including humans, non-human primates, and various animal species. There is ongoing research into the potential use of adenoviruses from non-human primates and other animal species for medical treatments. This is in addition to the well-researched human adenovirus types used in gene therapy.

Adenoviruses are divided into seven species based on their genetic features and the types of hosts they infect, showing their diversity. Human adenoviruses are classified into species A-G, with species B, C, and E most commonly associated with human infections. Adenoviruses have been found in various animal hosts, including non-human primates, cattle, horses, pigs, birds, and reptiles.

Recent studies have focused on isolating and characterizing novel adenoviruses from non-human primates, particularly rhesus macaques. Several new adenovirus isolates have been discovered, distinct from previously known human and simian adenoviruses. These novel rhesus adenoviruses belong to the poorly described adenovirus species G and exhibit strong innate immune responses. These isolates have a low prevalence in human populations. This makes them good candidates for gene therapy and vaccine development.

Advantages of Animal-Derived Adenoviruses

Adenoviruses from animal species offer several potential advantages in gene therapy and vaccine application. Firstly, humans have fewer antibodies against these adenoviruses. This reduces the risk of the virus being neutralized and increases the likelihood of successful gene delivery or immunization.

Secondly, animal adenoviruses may possess different cell targeting and immune-stimulating properties than human adenoviruses. This could enable targeted gene delivery or more robust immune responses for vaccine development.

Lastly, the genetic variances between human and animal adenoviruses can provide unique genetic diversity, allowing for exploring new vector designs and therapeutic applications.

Case Studies: Successful Adenovirus-Based Treatments

Clinical trials using adenoviruses are offering insights into its broad applications. Adenovirus-based gene therapy mainly focuses on single-gene disorders. These therapies introduce a correct gene copy to fix the underlying disorder. 

Notable efforts include trials for Cystic Fibrosis. These trials use adenoviral vectors to deliver a healthy cystic fibrosis transmembrane conductance regulator gene, potentially improving lung function. 

Hemophilia Trials use vectors to carry clotting factor genes VIII and IX for hemophilia A and B, respectively. Additionally, Familial Hypercholesterolemia trials use adenoviral vectors to deliver the low-density lipoproteins, or “bad” cholesterol receptor gene, aiming to lower cholesterol levels.

Adenoviruses also show promise in treating various cancers by targeting tumor cells while sparing healthy tissue. Current studies are looking at using adenoviral vectors to treat solid tumors and cancers. These vectors carry genes that can slow tumor growth, strengthen the immune system, or kill cancer cells.

Looking Ahead

Adenoviruses are versatile and practical tools in gene therapy and gene editing. They can infect many human cells and have high transduction efficiency, making them ideal for delivering therapeutic genes. As research progresses, the potential of adenoviruses in treating genetic diseases and cancers and developing vaccines is becoming increasingly apparent. Stay tuned for Part 4 of our series, where we will explore the exciting intersection of adenoviruses and CRISPR technology, diving into the transformative potential this combination holds for the future of gene editing and therapy.

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This story is part of a series on the current progression in Regenerative Medicine. In 1999, I defined regenerative medicine as the collection of interventions that restore tissues and organs damaged by disease, injured by trauma, or worn by time to normal function. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

In this subseries, we focus specifically on gene therapies. We explore the current treatments and examine the advances poised to transform healthcare. Each article in this collection delves into a different aspect of gene therapy’s role within the larger narrative of Regenerative Medicine. This piece is part of our subseries that delves into vectors for gene therapies.

To learn more about regenerative medicine, read more stories at www.williamhaseltine.com