Axial - Matrix #6 (non viral delivery)
Unique business models in life sciences
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Non viral delivery
Viral methods are the current consensus for gene therapy - positioned to cure many diseases but are currently limited by payload size and complexity and re-dosing (the immune system generates antibodies against a virus). New inventions increasing transfection and expression are allowing non-viral methods to become viable and overcome these limitations. With companies like Generation Bio, GuideRx, and GenEdit leading the way, non-viral delivery is increasingly becoming a possibility for new therapeutic modalities to reach patients and cure new indications that are inaccessible by viral approaches.
The major technical limitations or critical steps in attaining a successful gene therapy are categorized into:
Efficiency of vector transport and unloading into target cells
Perseverance
Activity
Immune response
Viral vector builders are paring away pieces of genes so the vectors become more stealth like and thus avoid detection from the body's immune system. Meanwhile non-viral vector architects are adding pieces (i.e. polymers, peptides) to their vehicles such as ligands to help the vectors reach specific tissues/cells with the advantages:
The chemical flexibility of non-viral systems means they are easier to modify
Simpler large scale production
Low host immunogenicity
Previously, low levels of transfection and expression of the payload held non-viral methods at a disadvantage. The efficiency of transfecting host cells is relatively high with viral vectors compared to non-viral methods. Recent advances in vector technology have generated molecules and techniques with transfection efficiencies similar to those of viruses. Ultimately, the best solution would be a capsule that mimics viruses with regards to specificity and efficiency without the side effects and increased size and dosing.
Non-viral vectors are simple in theory but complex in practice. Apart from intra- and extra-cellular barriers, many other challenges also need to be surmounted in order to increase the effectiveness of non-viral delivery. These barriers are categorized as production, formulation, and storage. For non-viral delivery, there are no one-size-fits-all solution, which is why in spite of various developments in liposome/polymer formulation and optimization, new compounds are constantly being proposed and developed.
Non-viral vectors are generally used to transfer following types of cargos:
Small DNA (oligonucleotides)
Large DNA molecules (plasmid DNA)
RNA (ribozymes, siRNA, mRNA)
Proteins (peptides, biologics)
However the application of non-viral delivery have been ignored for a long time because of their poor efficiency of delivery and thereby low transient expression/concentration of their cargo. With the limitations of current viral vectors (with AAVs having the most success due to their lower immunotoxicity), non-viral delivery has recently been revisited for commercial applications. Advances in efficiency, specificity, gene expression duration, and safety are leading to increased use of non-viral methods. As a result, there is still a large opportunity to develop non-viral vectors that fulfill all the ideal vector properties:
Cell/tissue specificity can be achieved by harnessing cell-specific functionality
Ease of production
Potential for repeat administration
Non-viral methods are generally viewed as less efficacious than the viral methods. So the opportunities for new companies to bring non-viral delivery are:
Translocation of the DNA particle to nucleus by membrane receptors and transgenic expression of it
Capacity to efficiently interact with serum components without losing the therapeutic material
Appropriate circulating time in the body and bio-distribution
Escape from immune system and macrophages
Targeting ability of the cell
Penetration through cell membrane barrier
Intracellular trafficking capacity (release from endosomes and escape from degradation by nucleases)
Nuclear import capability/persistence in nucleus
Maintaining gene expression (time-dependent)
Passage to succedenous cells (progeny cells)
Ability to transcript
The future will have a mixture of viral and non-viral delivery.
Have a nice day.