April 11, 2019

How does genetic material get delivered to the patient?

By Clive Glover, Cytiva

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.

Gene therapy holds promise to cure or alleviate symptoms of many different diseases. It 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 genetic material delivery due to their target cell specificity, relatively high target cell infectivity, and low toxicity upon infection.

Viral vs non-viral approaches

Viral vector

Viral vector genetic material 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’s this behavior and characteristics of viruses that makes them the most effective in transporting genetic material for therapy.

Non-viral vector

Several physical and chemical non-viral approaches 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 genetic material delivery 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 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 using 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 (LV)

Even though integrated solutions can offer substantial value to manufacturing processes, it requires experience and expertise associated with manufacturing process, equipment automation, and engineering for operational execution. The most proficient way of incorporating integrated solutions is to work with end-to-end solution providers who have skilled process experts and resources to manage the entire project. The provider also ensures the project is managed based on process requirements rather than fitting the process on selected equipment by offering compatible solutions.

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 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. 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 toxicity that can reduce undesirable therapeutic outcomes. Industrialized process platforms 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 are ready to take the next step towards commercialization.

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1Key Considerations for Gene Therapy Commercialization, Cell Culture Dish, September 12, 2018