Longevity Briefs: Gene Therapies Might Be Getting A Size Upgrade

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Our ability to reverse the ageing process in humans could be closely tied to innovations in gene therapy. Gene therapy is a technology that circumvents many of the limitations of conventional drugs. Gene therapies use the language of life (DNA or RNA) to instruct cells on exactly what proteins to make, or to shut down the production of harmful proteins. This means that if you sequence a patient’s genome, you can quickly develop a gene therapy tailor-made for them.

One of the major limitations of gene therapy currently is that some genes are really big – too big to fit inside the engineered viruses typically used to deliver them to human tissues. Lipid nanoparticles may offer larger carrying capacities, but come with their own set of problems. If we want to fully unlock the potential of gene therapy, we need to be able to deliver larger payloads.

What did the researchers do: In this study, researchers aimed to develop a virus with an expanded carrying capacity. They opted to use a type of virus known as a bacteriophage – a virus that only infects bacteria. The researchers added a coating to the phage that results in its engulfment by human cells.

A representation of how bacteriophages infect bacteria. Bacteriophages cannot infect human cells, so researchers had to package them in proteins that would lead to their engulfment.
*https://www.whatisbiotechnology.org/index.php/science/summary/phage-therapy/*

Key takeaway(s) from this research:

The phage’s carrying capacity was about 20 times larger than the largest conventional viral delivery systems.
The phage successfully delivered large genes and gene editing technology to human cells in culture.
Large vectors may be valuable for a holistic approach to human rejuvenation.

The phage was able to carry genetic material up to 171 000 bases long, which is about 20 times larger than the capacity of the largest conventional viral delivery systems. The researchers also showed that the phage could deliver genes to human cells in culture.

A table comparing the advantages and disadvantages of different viruses for delivering gene therapy, including carrying capacity (DNA insert size) in kilobases. Human gene therapies are most commonly delivered using an adenovirus or adeno-associated virus (AAV).
*https://bitesizebio.com/25147/comparing-viral-vector-expression-systems/*

They were able to deliver the dystrophin gene, one of the largest human genes, and one whose mutation is responsible for Duchenne muscular dystrophy. When they did, the cells were able to use that gene to produce the full length dystrophin protein. The phage could also be used for gene editing, and multiple genes could be edited simultaneously when phages were loaded with CRISPR/Cas9 editing machinery.

While these results are encouraging, we still don’t know how well the phages can perform in living humans. The treatment needs to be safe, of course, but it also needs to be able to reach the correct cells depending on what treatment is being delivered – a gene therapy intended to treat kidney disease won’t do much good if most of it ends up somewhere else in the body.

When it comes to slowing the ageing process, delivery systems with large capacities could be particularly valuable. Effective anti-ageing interventions will probably require many different processes to be targeted at once, so being able to deliver many different gene therapies simultaneously will make this process more straightforward.