Telomerase Gene Therapy May Treat Fibrosis via a Reduced Burden of Cellular Senescence
A number of research groups are quite enthusiastic about the prospects for telomerase gene therapy as a treatment for aging and numerous age-related diseases. This is based on more than a decade of work in mice, showing extended life spans and improved metabolism. Over the past few years, reversal of fibrosis via telomerase gene therapy has been demonstrated in mice. The evidence for this to be an approach worth bringing to the clinic continues to accumulate. Fibrosis is a disruption of tissue maintenance, associated with chronic inflammation, in which an inappropriate deposition of scar-like collagen takes place, degrading normal tissue structure and function. Today's research materials are the latest on this topic, in which scientists dig deeper into the mechanisms by which telomerase upregulation might be acting on fibrosis in the lung.
The primary function of telomerase is to extend telomeres, caps of repeated DNA at the ends of chromosomes. Telomere length shortens with every cell division, but only stem cells normally express telomerase and thus have the capability to maintain long telomeres. The vast majority of somatic cells in the body lose their telomere length until hitting the Hayflick limit, at which point their shortened telomeres trigger cell death or cellular senescence. All tissues are in a state of turnover, losing cells to the Hayflick limit, while replacements with long telomeres are generated by stem cells.
Telomerase upregulation might produce benefits in a number of ways. Firstly, if all cells express telomerase, then there will tend to be more functional cells in any given tissue, postponing age-related declines in function that occur due to a slowing of stem cell activity. A concern here is that this will allow damaged cells to function for longer, and thus raise cancer risk. That raised risk doesn't occur in mice with upregulated telomerase, possibly because immune system function is improved by telomerase gene therapy in the same way as other tissue function, and improved cancer suppression by immune cells outweighs the increased risk due to lengthening the telomeres of damaged and potentially cancerous cells. Whether or not the same balance of factors will occur in humans is still to be determined.
Secondly, telomerase upregulation may reduce the burden of senescent cells in tissues, both by preventing cells from replicative senescence, and by improving the operation of mechanisms that clear senescent cells. Senescent cells are important in aging, as demonstrated by the extension of life and reversal of age-related disease produced in mice via senolytic therapies that selectively remove these errant cells. Interestingly, senescent cells are strongly implicated in the progression of fibrosis, and their removal has been shown to reverse the condition in mice. In the research noted here, telomerase gene therapy reduces measures of senescence in fibrotic lungs. It is entirely plausible that this is the primary mechanism by which increased telomerase activity reverses fibrosis.
Researchers pave the way for a future gene therapy to reverse pulmonary fibrosis associated with ageing
Idiopathic pulmonary fibrosis is a potentially lethal disease for which there is currently no cure and that is associated with certain mutations or advanced age. Resesarchers had previously developed an effective therapy for mice with fibrosis caused by genetic defects. Now they show that the same therapy can successfully be used to treat mice with age-related fibrosis. The treatment tested in mice is a gene therapy that activates the production of telomerase in the body. Telomerase is an enzyme that repairs the telomeres at the end of chromosomes.
The new study describes the effects of ageing on lung tissue in detail. One such effect is that alveolar type II cells stop doing their job. In addition to regenerating tissue, these cells produce and release a lipid-protein complex called pulmonary surfactant that facilitates the mechanical work done by the lungs. "Lung tissue must expand when we breathe in, six to ten times per minute, which means a great deal of physical effort. Pulmonary surfactant plays an important role in lubricating lung tissue, retaining its elasticity, and reducing the amount of work required to expand and contract it. If type II pneumocytes fail to regenerate, the surfactant is not produced, which results in lung stiffness and fibrosis."
In 2018, researchers developed a gene therapy that reversed pulmonary fibrosis in mice lacking the telomerase gene. This therapy was based on activating telomerase expression temporarily. A virus used as a telomerase gene carrier was injected intravenously into the mice. The effect - alveolar type II cells with long telomeres - was temporary, but lung tissue regeneration was successfully induced. The same therapy was now used in aging mice. And it worked in them too. "The telomerase-activating gene therapy prevented the development of fibrosis in all mice, including the ones without genetic alterations that only underwent physiological ageing."
Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging
We determined the impact of AAV9-Tert gene therapy in rescuing DNA damage, apoptosis, and senescence in Tert+/+ and Tert-/- lungs treated with either AAV9-Tert or AAV9-null virus particles. We found that both Tert+/+ and Tert-/- mice treated with AAV9-Tert showed significantly decreased numbers of γ-H2AX-positive cells in the lung parenchyma compared with the corresponding cohorts treated with the null vector, indicating decreased DNA damage upon telomerase treatment. Similarly, we detected significantly decreased numbers of activated caspase3-positive cells in the alveolar parenchyma of both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector. Interestingly, increased senescence as detected by p16-positive cells specifically in the case of aveolar macrophages was also rescued in both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector.
Finally, by performing double immunostainings with the proliferation marker Ki67 and the specific markers for alveolar type II cells, club cells, and aveolar macrophages, we observed that proliferation of alveolar type II cells, club cells, and aveolar macrophages was significantly increased in both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector. Interestingly, the number of SOX2-positive differentiating club cells was also significantly reduced in Tert+/+ and Tert-/- lungs upon telomerase gene therapy.
Finally, to address whether treatment with telomerase gene therapy also prevented expression of proinflammatory and anti-inflammatory markers, we determined mRNA expression of Tnf, Il1b, Il6, Il4, Il10, and Il13 in total lung extracts from Tert+/+ and Tert-/- mice. We observed significantly decreased expression of these markers in both Tert+/+ andTert-/- mice treated with AAV9-Tert compared with those treated with the null vector.
It could also be stem cell loss or exhuastion rather than senescent cells driving fibrosis, or given the effects of senloytics both.
It would be good to see the experiment repeated with a placebo, senolytic only, telomerase only, and combinded arms to see if any one does better under controlled conditions.
Does anyone think this method might also work for fibrosis of tissues that have been exposed to radiation during cancer therapy? I had this therapy and it was absolutely barbaric and worthless. It left me with an area of skin that is non-elastic and rigid. Fibrosis! Please comment on that.
I am inquiring about your gene therapy for radiation fibrosis. Do you know anyone that can do this?