Additional Evidence to Demonstrate that Telomerase Gene Therapy Does Not Increase Cancer Risk in Mice

In recent years, researchers working on forms of telomerase gene therapy have produced evidence to show that increased levels and activity of telomerase does not raise cancer risk in mice. The open access paper and publicity materials noted below report the latest example. Extra telomerase increases the sort of activities that are beneficial in the context of improved regenerative capacity, but might be thought to raise the risk of cancer when they take place in the damaged environment of old tissue. This means more stem cell activity, more cellular replication, and so forth.

Somatic cells are limited in the degree to which they can replicate by the length of their telomeres, repeated DNA sequences at the ends of chromosomes. A little of that length is dropped with each cell replication, and a cell with short telomeres will become senescent or self-destruct, and in either case cease replicating. The primary function of telomerase is to extend telomeres, so the operation of telomerase in somatic cells will act to push them past their evolved limits to replication. Stem cells, on the other hand, naturally deploy telomerase to bypass the telomere countdown and retain the ability to replicate indefinitely.

All higher animals depend upon this split between a small number of privileged cells and the vast majority of limited cells. It is the primary means by which incidence of cancer is kept to a low enough rate, and pushed off far enough into later life, for evolutionary success. Near all cells that suffer random DNA mutation are somatic cells, and thus are removed from circulation long before they can become damaged enough to be a threat. Unless they are full of telomerase, and replicating for far longer, in which case the odds change for the worse.

Why, then, does telomerase gene therapy in mice fail to increase cancer risk? In fact in some studies it dramatically reduces cancer risk. One theory is that the increased cellular activity and replication in the immune system more than offsets the increased risk elsewhere. Immune cells are an important line of defense against cancer, seeking out and destroying cancerous cells. Cancer risk correlates fairly well with measures of immune system decline with age.

Does this mean that we should embrace telomerase gene therapies for human use, as way to enhance regeneration in the damaged tissues of old individuals? Not yet, I think, or at least not yet if we are cautious. Mice have very different telomere and telomerase dynamics when compared to humans. It is still possible that the balance of evolved cellular metabolism plus added telomerase works out to less cancer in mice, but more cancer in humans. There is work yet to be done, some of which might take the form of more brave individuals self-experimenting with gene therapies, if the last few years are any guide.

Researchers prove that gene therapy vectors carrying the telomerase gene do not increase the risk of cancer in cancer-prone mouse models

For years now researchers have been investigating the possibility of using the enzyme telomerase to treat pathological processes related with telomere shortening, as well as diseases associated with ageing - cardiovascular and neurodegenerative diseases, among others - and even the ageing process itself. In 2012, they designed a highly innovative strategy: a gene therapy that reactivates the telomerase gene using adeno-associated viruses (AAV). These gene therapy vectors do not integrate in the genome of the host cell, thus telomerase only performs its telomere-reparative actions during a few cell divisions before the vector is diluted out. In this manner, a potential risk associated with the activation of telomerase, such as promoting cancer, it is minimized. But to what extent?

The paper being published now specifically tackles this question by applying gene therapy to an animal model, a mouse, which reproduces human lung cancer and which, therefore, already has a greater risk of developing this disease. The results are negative: "The activation of telomerase by means of this gene therapy does not increase the risk of developing cancer", not even in these mice, where tumours are forced to appear in a relatively short time.

"These findings suggests that gene therapy with telomerase appears to be safe, even in a pro-tumour context. In our research, we were already seeing that this gene therapy does not increase the risk of cancer, but we wanted to conduct what is known as a 'killer experiment', an experiment that creates the worst conditions for your hypothesis to hold true; if it survives even under those circumstances, the hypothesis is truly solid. That is why we chose these mice; they are animals that spontaneously develop a type of lung cancer that is very similar to the human form, which normally never appears in normal mice. We can't think of any other experiment that would provide a better demonstration of the safety of this therapy".

AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer

The ends of our chromosomes, or telomeres, shorten with age. When telomeres become critically short cells stop dividing and die. Shortened telomeres are associated with onset of age-associated diseases. Telomerase is a retrotranscriptase enzyme that is able to elongate telomeres by coping an associated RNA template. Telomerase is silenced after birth in the majority of cells with the exception of adult stem cells. Cancer cells aberrantly reactivate telomerase facilitating indefinite cell division. Mutations in genes encoding for proteins involved in telomere maintenance lead the so-called "telomere syndromes" that include aplastic anemia and pulmonary fibrosis, among others.

We have developed a telomerase gene therapy that has proven to be effective in delaying age-associated diseases and showed therapeutic effects in mouse models for the telomere syndromes. Given the potential cancer risk associated to telomerase expression in the organism, we set to analyze the effects of telomerase gene therapy in a lung cancer mouse model. Our work demonstrates that telomerase gene therapy does not aggravate the incidence, onset and progression of lung cancer in mice. These findings expand on the safety of AAV-mediated telomerase activation as a novel therapeutic strategy for the treatment of diseases associated to short telomeres.

Comments

The question that we should ask ourselves is why the mice are so susceptible to cancer. They don't live long and don't have enough time for random dna damage. They might have a higher rate of oxidative stress but even that should take longer than a couple of years to develop into cancer. It is like that are genetically predisposed to ♋ cancer.

Posted by: Cuberat at August 22nd, 2018 12:16 AM

Yet more good work from Blasco.

Remember aav-tert therapy is not immortalizing cells (one of the 3 or 4 barriers they have against cancer), only resetting them back to a youthful length.

On the subject of DNA damage, longer telomeres will mean a cell is better at identifying and repairing DNA damage. (Anyway, it is not certain DNA damage is the cause of cancer).

As for mouse and human telomere dynamics being very different - I am not so sure that is true. Both shorten with age, and both accumulate short telomeres with age, as defined as a percentage of their initial length. Just because mice telomeres do not get completely used up doesn't mean telomere shortening on its own does not cause havoc (https://www.ncbi.nlm.nih.gov/pubmed/23022483).

Posted by: Mark at August 22nd, 2018 3:48 AM

I think there was a study shutting that longer telomeres increased the risk of lung cancer. So boosting the telomerase or tripling the groomers length across the board is not all free ride ..

Posted by: Cuberat at August 22nd, 2018 8:01 AM

This is great news. That means the stuff AGEX/Salk/George Church and Scripps are working on should have application.

I'm wondering if the 'big plan' is to use re-programming for the bulk of the rejuvenation, and then damage repair for the remainder. That would probably go a long way. I could be wrong... I work more on the people/policy/economics side of this transformation. I'll let Reason/Aubrey/George etc work on the nuts and bolts :)

Posted by: Mark Borbely at August 22nd, 2018 11:56 AM

@Cuberat - yes, in smokers. Stay off the mutagens and you should be fine. Interestingly the same study found higher cancer incidence in those smokers with shorter average telomeres also. So it's not a case of having as long telomeres as possible. Just having them at the right length (i.e. why you had at 20, say).

Posted by: Mark at August 22nd, 2018 1:01 PM

As I predicted a few years ago, the application and utility of telomerase gene therapy are becoming ever more apparent. The results here please me no end.

Posted by: Steve Hill at August 24th, 2018 9:27 AM

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