Targeting Ageing With Gene Therapy – Part 3: What’s Stopping Us?

In the previous part of this series, we looked at some of the different strategies at our disposal to target the ageing process using gene therapy. There are quite a lot of exciting possibilities and many that have been shown to work in animal models, so why don’t we have working gene therapies for age-related diseases yet? That’s what we’re going to talk about in this final part.

The Devil Is In The Delivery

You may remember from part 1 that designing the ‘genetic’ part of the gene therapy is only half the battle – the gene therapy, whether it’s gene editing technology like prime editing or an mRNA molecule designed to turn off a specific gene, needs to be delivered to the cell nucleus where the DNA resides. It is also essential that the gene therapy reaches the correct cells. This is where problems are most likely to occur, because all of our current techniques for delivering gene therapies have significant limitations.

Immune reactions: Most currently available delivery methods are recognised by the immune system to some extent. This creates an immediate safety problem – the higher the gene therapy dose, the more likely it is to trigger an immune reaction that could prove dangerous for the recipient. However, getting an anti-ageing gene therapy into most cells in the human body is likely to require large doses.

Even if safety problems are overcome, the immune system still poses a problem since immune cells may destroy the gene therapy before it reaches the target cells. In the case of some delivery systems, this problem worsens over time because the immune system learns to recognise and swiftly eliminate the particles carrying the gene therapy, just as it would learn to recognise a pathogen. To overcome these problems, we will need to refine existing delivery mechanisms or develop new ones that are less easily recognised.

Tissue specificity: Different tissues age in different ways and at different rates. This adds another layer of complexity to the delivery of gene therapy because it is essential that the right gene therapy reaches the correct target. Some delivery systems are easier to design to reach specific organs than others, but could be unsuitable for other reasons such as cargo size.

Personalisation: Just as different tissues do not age in the same ways, neither do people. Genetic and environmental differences mean that different approaches to targeting ageing may be optimal for different people. Gene therapy makes personalisation easier as, in theory, whatever gene therapy an individual needs can simply be loaded into an already-proven delivery system. We are a long way from this in practice, however.

Manufacture: Just because a gene therapy works in a lab or small clinical trial, this doesn’t mean it will be practical to deliver to a large population. Some delivery systems are hard to manufacture at large scale, though methods are improving.

Genetic risks

Editing errors: A concern that many people have with anything regarding genetics is unintentional and permanent modifications to the DNA. While the way in which this risk is portrayed is sometimes overly alarmist, this is a genuine problem with some types of gene therapy. Gene therapies that involve integrating new genetic material into the DNA run the risk of inserting that material in the wrong place, disrupting existing genes. This isn’t just a hypothetical problem – early attempts to treat severe combined immunodeficiencies (SCID) with gene therapy resulted in leukaemia in some recipients because it resulted in the activation of a cancer-causing gene. This will become less of a risk as the precision of gene editing techniques continues to improve.

Reprogramming: In part 1, we also covered gene therapies designed to erase some of the epigenetic modifications responsible for ageing. As a reminder, epigenetic modifications are alterations to the DNA molecule that don’t change the genetic code itself, but rather how it is read. Epigenetic reprogramming runs the risk of reprogramming a cell too far, causing it to become a stem cell. This risk can be overcome by carefully controlling the level of expression of reprogramming factors. However, that’s not the only risk – reprogramming can also lead to the inactivation of tumour-suppressing genes that previously got switched on in response to genetic mutations that increase cancer risk.

Though these challenges remain, the future of gene therapies targeting ageing looks promising. Gene therapy techniques continue to be refined and new delivery methods worked on. Some human clinical trials are already taking place, such as the safety test for the telomerase gene therapy we mentioned at the end of part 2. Unfortunately, it is challenging to get regulatory approval for any treatment targeting ageing itself, which is why some companies choose to conduct clinical trials in regions with less strict regulations. People should have the right to do what they think is best for their health, so long as they are adequately informed of the risks – this sadly doesn’t always happen in the case of these less regulated trials.