Viral-vector gene therapies use Adeno-associated virus as a delivery vehicle to introduce particular DNA sequences—regulatory RNAs, encoding genes and therapeutic substrates into cellular machinery. Adeno-associated viral vectors are an important tool to deliver gene therapies to patients to modify the defective gene with a functional one. These AAV vectors are used in the treatment of chronic diseases such as cancer, cystic fibrosis, and retinitis pigmentosa. Today, researchers are focusing on the development of gene therapies to treat diseases such as spinal muscular atrophy. Technological advancements in the pharmaceutical industries have drawn interest in gene therapies because of their potential advantages.
The future of gene therapies is promising as it is expected to experience an economic boost to meet with rising demand for these vectors. The global AAV vector market is expected to grow from $1.9 billion in 2022 to $ 11.1 billion by 2035, exhibiting a CAGR of 14% in future, according to Roots Analysis. Moreover, various pharmaceutical and biotechnology companies hold a broad portfolio of gene therapy products in their pipeline that is expected to boost the AAV vector market in the coming years.
AAV Vector Overview
Adeno-associated viral vector is a non-enveloped virus that is developed to deliver a functional gene/DNA to target cells with utmost accuracy using various strategies. The AAV is specifically used in clinical trial experiments to generate recombinant AAV fragments containing DNA. This is considered a safe strategy to deliver gene therapies for a broad range of therapeutic applications. The Adeno-associated virus is rapidly becoming the most popular gene delivery method for gene therapies because it is non-pathogenic and has shown efficient transgene expression in different types of cells, making it ideal to be engineered for specific gene functionality.
However, the success of AAV vector technology is illustrative of the current state of viral-vector gene therapy. As more gene therapies have reached clinical trials, it is evident that several technological challenges have to be overcome to unlock the complete potential of viral vector gene therapies. Therefore, to meet technical challenges, the pharmaceutical industry has come up with innovative strategies and advanced technology that address all the vital aspects associated with the development of viral vector gene therapy.
AAV Technology: Challenges to Comprehend the Potential of Viral-vector Gene Therapies
The decades of clinical research have resulted in the development of current-generation viral-vector gene therapies. Despite the significance of viral vector gene therapy, there are three fundamental challenges that restrict the potential use of AAV vectors.
■ Preexisting Immunity
The success of AAV gene therapy depends on its capability to pass the multiple lines of defense positioned by the immune system. Viral capsids and transgenes products themselves are recognized as foreign particles, providing an opportunity for the immune system to limit the efficacy of viral gene therapy. Presently, most of the viral-vector gene therapies have been derived from harmless viruses. Many patients may have past exposure to the same virus and have preexisting immunity against the virus because of which immune system may not respond to gene therapies.
■ Safety Concerns Of Using High Dose Gene Therapies
Currently, viral-vector gene therapies require administering a substantial amount of dosage to patients, especially for the treatments for systemic disorders. Nevertheless, administering a high dose of therapies to a patient has been associated with unfavorable adverse events. Furthermore,the production of large quantities of these dosages is expensive and challenging.
■ Regulation of Transgene Expression
To maximize the success rate, early viral-vector gene therapies have opted to add regulatory elements such as promoters that control gene expression. However, the addition of regulatory genes may possess significant drawbacks, specifically overexpression or wrong expression of the transgene which may contribute to the development of toxicities and inflammation.
Innovation in AAV Manufacturing Techniques to Address Gene Therapy Challenges
To overcome the challenges associated with AAV, several pharmaceutical companies have established innovative AAV vector technology solutions. The primary focus is on gene therapy products and development process parts. These innovations also address the core challenges that restrict the usage of gene therapies.
■ Reengineered Capsids
The viral capsid plays an essential role in gene therapies. It not only determines specific cells that are targeted but also helps to understand effectiveness and rejection of the gene therapy by the immune system. Moreover, viral capsid also significantly influences the stability of the viral vector throughout the manufacturing process and impacts storage and distribution requirements. Most of the virus vectors that are used today for therapies are isolated from natural resources so a patient might have preexisted immunity against virus vectors which ultimately leads to the rejection of therapy by the immune system.
To overcome the problem of preexisting immunity, many companies have focused on reengineered capsids that are derived from viruses present in other species. The drug developers are modifying the characteristics of the capsid to provide immediate benefits from the therapy.
For instance, AAVrh 74 and AAV8 capsids have been isolated from AAV serotypes and modified by drug developers to use in various AAV vector gene therapies.
■ Engineered Vectors
R&D in gene therapy is increasingly concentrating on vector engineering. Adenovirus and lentivirus vectors are frequently simpler to construct than AAV vectors because they can package larger amounts of DNA. However, AAV-vector designs are also starting to use cutting-edge vector components.
In general, vector engineering tries to enhance transgene expression and lessen the viral vector’s immunogenicity. Codon optimization is one method that accomplishes both objectives. In this method, modifications in the vector sequence are investigated to get rid of immunogenic sequence motifs while strengthening the transgene’s expression.
■ Technological Advancement in Manufacturing Processes
The vector-based gene therapy provides significant benefits in the treatment of rare and chronic diseases. This is the reason gene therapies have begun to expand at a global level to help patients live a quality life. Earlier, manufacturing processes of gene therapy were not regulated to meet the demand for large-scale production. One of the biggest challenges that companies have faced in designing vector-based therapies is the presence of large amounts of empty capsids that have no active gene.
To overcome the challenge, pharmaceutical companies have adopted two approaches in manufacturing processes: engineered cell lines that help to pack complete capsids with active genes more efficiently and introduce advanced methods for the separation of full capsids and empty capsids based on particular properties such as molecular weight and charge.
■ Enhanced Pre-Treatment Protocol
Besides creating engineering vector capsids and vectors, a system approach has been taken to reduce the immune system regarding the detection of the gene involved. Gene therapy consists of co administration of immunosuppressive agents to combat the problem of preexisting immunity. Several researchers are focused on experimenting with targeted immune suppressive drugs such as rituximab (Rituxan®), a form of monoclonal antibody that helps to reduce the formation of memory B cells. Similarly, another approach that is followed to enhance the pre-treatment regimen is the implementation of CRISPR-based repression to inhibit the generation of neutralizing antibodies. The approach helps the patient to receive multiple doses of gene therapy using a similar vector backbone.
AAV Manufacturing Companies: Several Manufacturers Have Developed AAV Technology to Meet Current Demand
The growing demand for gene therapies pushes AAV manufacturing companies to develop more Adeno-associated viral vectors to meet with current demand. At present, more than 80 AAV technology manufacturers have the potential to manufacture these vectors. Most of these companies either have clinical batch manufacturing potential or preclinical manufacturing units to design AAV therapies.
At the same time, 43% of AAV vector manufacturing companies have the advanced technology and operating units to meet the large-scale commercial manufacturing requirement. The top pharmaceutical companies like Thermo Fisher Scientific launched Gibco™, which is an AAV-Max Helper AAV Production System, in November 2022.
In October 2022, Charles River Laboratories launched a nAAVigation platform that supports AAV vector manufacturing. This company claims to reduce the time between process development and large-scale GMP manufacturing by 55%. The technological advances allow companies to develop AAV technology platforms for efficient vector manufacturing and support the AAV vector market.
AAV Market Trends: Recent Partnerships and Collaborations
With the rising demand for AAV vectors, multiple collaborations and partnerships have been established between key players. Commercialization agreements and product development are the two most popular partnership models used by AAV-based gene therapy developers for partnership. The goal of engaging in a partnership is to enhance AAV vector drug manufacturing.
▪ In May 2023, the Foreg Biologics, one of the top manufacturers of gene therapies, announced a manufacturing and gene therapy development collaboration with Labcorp, the global life sciences company. The collaboration provides access to GMP (Good Manufacturing Practices) and drug development services to the gene therapy clients so they can have better accessibility to the services for mediated gene therapy programs.
▪ In February 2022, SIRION Biotech, the leading developer of viral vector based gene therapies entered into a joint agreement with Centre for Genomic Regulations, an advance biomedical research to develop a novel Adeno-associated virus vector for a gene therapy to treat Type 1 and 2 Diabetes by targeting specific pancreatic cells.
The rising interest in gene therapies has further accelerated the growth of the AAV vector market. The market growth has been evident from patents that have been filed for the protection of intellectual property associated with AAV technology. Considering the ongoing partnerships and trends of Adeno-associated viral vectors, we believe the market will expand at a healthy CAGR in future.
Future Perspective of AAV Vector
Overall, the early success of viral-vector gene therapies in treating chronic diseases brings revolution to the healthcare sector. The widespread adoption of vector-based therapies and advances in biotechnology demonstrate that more solutions are on the way to treat diseases. The pharmaceutical companies are leveraging the latest technology and tools to upgrade their AAV vector platforms so they can provide more vectors-based therapies.
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