6 Ways to Engineer Adenoviruses for Gene Therapy and Vaccines

(Posted on Monday, June 24, 2024)

Once perceived as mere pathogens, adenoviruses have transformed remarkably, becoming indispensable allies in the fight against genetic disorders. In an era where medical innovation is paramount, adenovirus gene therapy is a beacon of hope, offering new avenues for combating genetic disorders through vaccines, gene carrier therapy, and groundbreaking CRISPR technology. 

This piece will explore the nature of adenoviruses, shedding light on their crucial role in modern medicine, including gene therapies, and the unique blend of challenges and breakthroughs that shape their journey in advancing medical treatments.

What Are Adenoviruses and Why Are They Important?

Adenoviruses are a diverse group of viruses known for their ability to cause a wide range of illnesses, including respiratory infections, conjunctivitis, and gastroenteritis. One of the distinguishing features of adenoviruses is their unique capacity to infect both dividing and non-dividing cells. 

In gene therapy, adenoviruses can be modified to transport and deliver functional genes to cells with defective or missing genes, potentially treating various genetic disorders. Moreover, adenoviruses can act as vectors to transport antigens from pathogens in vaccine development, eliciting a robust immune response without causing disease.

This innovative adenovirus-based mRNA vaccine approach has been particularly significant in developing vaccines for COVID-19, prompting the body to mount an effective immune response. Adenovirus-based mRNA vaccines offer several advantages. They are safe, as they do not contain any live viruses that could cause disease. They are also highly effective, as they can be designed to target specific pathogens. Unlike traditional vaccines, which rely on live attenuated viruses to stimulate the immune system, mRNA vaccines do not use live viruses. Instead, they instruct the cells to produce specific proteins that mimic the structure of the virus and trigger an immune response. 

The Different Types of Adenoviruses and Their Host Range

Adenoviruses can infect various hosts, including humans, non-human primates, rodents, and other mammals. The virus’s capacity to infect specific hosts depends on its ability to bind to particular receptors on the surface of host cells. In the case of human adenoviruses, the primary receptor is the coxsackievirus and adenovirus receptor (CAR), which is widely expressed on epithelial cells in the respiratory and gastrointestinal tracts. Besides CAR, some adenovirus serotypes can interact with other cell surface molecules, such as integrins, scavenger receptors, and heparan sulfate proteoglycans, expanding their ability to infect host cells. This versatility in receptor usage allows adenoviruses to infect various tissues and cell types, making them suitable vectors for targeting different body parts in gene therapy applications.

Over 50 adenovirus serotypes can infect humans, grouped into seven species labeled A through G. Each species varies in its ability to cause disease. For example, species C adenoviruses are linked to respiratory illnesses like the common cold. In contrast, species D adenoviruses are associated with “pink eye.” Species B adenoviruses cause severe respiratory infections and can affect the urinary tract. On the other hand, species F adenoviruses are primarily associated with acute gastroenteritis.

Understanding adenovirus differences is essential for developing targeted treatments and vaccines. This knowledge helps identify the best viral vectors for specific therapies and predict infection outcomes. Modifying adenovirus fiber proteins can alter their host range, allowing for tailored gene therapies that enhance precision and efficacy.

The Structure of the Adenovirus

Central to the adenovirus’s success as a gene therapy vehicle is its unique structural composition, a feat of biological engineering. The adenovirus capsid is composed of hexon, penton, and fiber proteins. This capsid is not just a protective layer but a sophisticated mechanism enabling the virus to breach host cells precisely.

Caption: ​​Adenovirus structure. A. Virion structure. B. Penton base’s side and top views C. Fiber structure and receptor binding sites.

The adenovirus capsid comprises hexon proteins, which form a sturdy framework for the virus, providing stability and protection. In contrast, the penton proteins are positioned at the corners of the capsid, contributing to its overall structure. Additionally, the fiber proteins protrude from the capsid and play a crucial role in helping the virus attach to and enter host cells, thereby increasing its ability to infect and replicate.

Caption: ​​Adenovirus capsid structure. A. General view of the HAdV-C5 capsid. B. Zoomed in views on the asymmetric unit. 

The intricate capsid structure is crucial for the effectiveness of adenovirus in gene therapy. The major and minor proteins that comprise the capsid play a vital role in encapsulating and protecting the virus’s genetic material. Importantly, encapsulating adenoviral DNA ensures its separation from the host genome, reducing the risk of insertional mutagenesis, a significant concern in gene therapy. 

Their capacious genome sets adenoviruses apart in gene therapy, allowing them to bear larger genetic payloads than other viral vectors. This larger genome capacity broadens the scope of diseases that can be treated through gene therapy, offering potential cures to a broader range of genetic disorders. These unique properties lend to their efficiency in delivering therapeutic genes into human cells. Adenoviruses can also infect both dividing and non-dividing cells, making them versatile tools in gene therapy.

Looking Ahead

Adenovirus gene therapy is at a pivotal point, with its applications in vaccines, gene carrier therapy, and CRISPR technology showcasing the dynamic interplay between biological innovation and medical advancement. While challenges remain, the ongoing research and development efforts promise to unlock new possibilities for precision therapies, enhancing the lives of those affected by genetic disorders.

As we continue to explore the vast potential of adenoviruses in gene therapy, the promise of a future where genetic diseases can be addressed more effectively and safely becomes increasingly tangible. Stay tuned as we venture further into uncovering the precision therapies and trial successes that lie on the horizon.

—————-

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