How Does Genetic Material Get Delivered to The Patient?
April 11, 2019
Delivery of Genetic Material for Gene Therapy
Gene therapy holds promise to cure or alleviate symptoms of many different diseases.
Gene therapy can be broadly broken down into two categories depending on whether the genetic modification takes place in vivo or ex vivo. This, along with the length of genetic material being introduced, the cell type being targeted, and whether the therapy’s efficacy requires integration of the genetic material into the patient’s genome, determines which vector is best suited.
Viruses are a popular choice for gene delivery due to their target cell specificity, relatively high target cell infectivity, and low toxicity upon infection.
Viral Vs Non-Viral Approaches
Viral vector delivery systems are the most popular technique currently used to deliver therapeutic material for gene therapy. Nearly two thirds of clinical trials are conducted using a variety of viral vectors1.
By nature, the life cycle of a virus includes the process of infecting a cell and introducing genetic material for replication. It is this behavior and characteristics of viruses that makes them the most effective in transporting genetic material for therapy.
Several physical and chemical non-viral approches are being studied at present to identify their advantages of delivering larger genes and reducing concerns associated with biosafety. However, these non-viral vector approaches currently demonstrate results that are less efficient in delivering genetic material than viral approaches. Non-viral vectors provide short term benefit compared to viral vector.
Characteristics of Commonly Used Viruses for Gene Therapy
Historically, retroviral and adenoviral vectors have been the most commonly used viruses for therapeutic purposes. However, safety and the improved target tissue expression profile of adeno-associated virus (AAV) and lentivirus (LV) have meant that these viruses are currently the main two viruses used in clinical trials.
Adeno-Associated Virus (AAV)
AAV vectors are the most widely used viral vector system in current clinical development for in vivo gene therapy. There are several benefits of AA viral vectors.
- It is not capable of causing disease
- It is generally well tolerated by the human body, with a low inflammatory response
- It does not integrate into the host cell genome, and mostly remains episomal.
The main disadvantage of AAV is its low packaging capacity, when compared to other viral vectors, which prevents the delivery of larger genes.
Lentivirus is most the frequently used viral vector for ex vivo gene therapy. A key benefit of LV, compared to retrovirus, is that it can transduce gene in both dividing and and non-dividing cells.
The various viruses that are in clinical use have different characteristics that make them differentially suited for different modes of gene therapy. These are summarized in the table above. Notably, the viruses also have different physical characteristics which has important implications for how the virus is manufactured.
The primary choice of gene delivery system will be dictated by a combination of the type of cells being targeted, the need for an integration, and the size of the gene being inserted. Where choices remain, some vector systems carry a lower risk of toxity that can reduce undesirable therapeutic outcomes and others have proven, industrializable process platforms that can simplify and accelerate the process development.
Whatever the choice, once the vector gene sequence is fixed and the master cell bank is created, you’re ready to take the next step towards commercialization.
1 Key Considerations for Gene Therapy Commercialization, Cell Culture Dish, September 12, 2018.
Clive Glover – Director, Cell & Gene Therapy
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