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Cellular Senescence as a Contributing Cause of Osteoarthritis

A fair few good scientific papers on the role of cellular senescence in the progression of osteoarthritis have emerged in the last year. Given that UNITY Biotechnology aims to initially trial senolytic therapies to clear senescent cells as a treatment for inflammatory joint diseases, a list in which osteoarthritis features prominently, and that the UNITY principals now have quite a lot of funding to work with, I expect that we'll be hearing a lot more on this topic over the course of the next few years. There is nothing quite like the existence of a funded company in a field to spur a great deal more investment in related research from all sources. The rate at which reviews of the relevant science are published tends to increase as well, with the paper linked below as an example of the type.

Senescent cells accumulate in tissues with age, and that accumulation is thought to be one of the causes of degenerative aging. While the immune system tends to destroy most of the senescence cells that fail to destroy themselves, its declining effectiveness in later life helps to ensure that the count of senescent cells keeps rising. In small numbers these cells are harmless; they have a role in wound healing, senescence followed by destruction is the normal end state for all somatic cells that reach the Hayflick limit, and senescence in response to damage or toxic stress helps to prevent cancer by removing those cells most at risk. Senescent cells secrete a potent mix of signal molecules, however, and when present in larger numbers this senescence-associated secretory phenotype (SASP) produces considerable harm. In the case of conditions driven by inflammation, or with strong inflammatory components, such as osteoarthritis, perhaps the most relevant aspect of cellular senescence is that the SASP includes pro-inflammatory signals. Senescent cells generate greater local inflammation, and more of all the consequences that follow on from that.

That rising inflammation has such an important role in the progression of many age-related conditions, and that senescent cells are a notable source of inflammation, are reasons to think that targeted removal of senescent cells should be broadly beneficial for human patients. The sooner that senolytic therapies can be brought to the clinic, the better. Currently the near term prospects seem quite hopeful, since the initial brace of senolytic drug candidates are forms of chemotherapeutic, already well characterized for human use as a result of cancer treatment trials, and their mechanisms of action comparatively well understood. If they can be used at lower dosages, at which the serious side-effects of cancer chemotherapy can be avoided, then we may well see responsible medical tourism for senescent cell clearance a couple of years from now. For those who want to wait for treatments with few to no side-effects, there is always the work being undertaken by Oisin Biotechnologies, which will likely follow on to clinics a few years thereafter.

Cellular senescence in osteoarthritis pathology

Osteoarthritis (OA) is the most prevalent disease of synovial joints (around 4.7% of global population for knee and hip OA alone), afflicting many millions worldwide with pain and disability, and thus represents an enormous healthcare and socioeconomic burden. Advancing age is a major risk factor, thus the burden of OA is set to increase dramatically as populations continue to age. A joint affected by OA exhibits progressive degeneration of the articular cartilage, formation of bony peripheral outgrowths (osteophytes), changes in subchondral bone and thickening of both the synovium and ligaments, and in many cases synovial inflammation (synovitis), which is thought to be an important driver of early pathology. Pathologic roles for multiple tissues in deteriorating joint function therefore define OA as a whole joint disease, driven by various biomechanical and inflammatory factors. There are currently no treatments available to effectively prevent or reverse progressive joint damage; therefore, new and innovative treatments are urgently required to improve treatment options. This will require continued improvements in our understanding of the molecular mechanisms underlying OA pathology.

Senescent cells secrete a variety of inflammatory cytokines, growth factors and many more soluble and insoluble factors known as the senescence-associated secretory phenotype (SASP). These factors are secreted into the cell microenvironment, with cytokines such as IL-6 and IL-8 enforcing the stable growth arrest of senescent cells. Various features of senescent cells, such as the SASP, can cause damage to surrounding tissue. SASP secreted by senescent cells can alter the tissue microenvironment, while the senescence of stem or progenitor cells can impair tissue regeneration. Over the past decade, many studies have linked cellular senescence to aging and age-related pathologies, thus leading to an overlap in research between the fields of disease processes and gerontology.

Although there are multiple joint tissues and cell types involved in OA pathology, chondrocytes have been the focus of the vast majority of studies to date that address a role for senescence. Chondrocytes are the only cell type present in articular cartilage, a highly specialized avascular and aneural tissue whose structural and mechanical properties are largely defined by the two predominant extracellular matrix (ECM) components, type II collagen, and aggrecan. Chondrocytes are responsible for producing and maintaining this ECM and receive nutrients and external chemical signals from the synovial fluid via secretions of fibroblast-like synoviocytes of the intimal synovial layer.

It is thought that cellular senescence may play a significant role in the pathology of OA, with OA chondrocytes exhibiting a variety of senescent-associated phenotypes. Despite recent traction for views of OA as a whole joint disease rather than merely dysfunctional cartilage, chondrocytes remain regarded as key players in OA pathology and are understood to exhibit during disease a perturbation of the normal balance between synthesis and degradation of extracellular matrix (ECM) components. This involves upregulating the production of matrix-degrading metalloproteinases such as MMP-13, exogenous activity of which was sufficient to recapitulate key OA features in mice. Senescence of chondrocytes would be expected to lead similarly to shifting of the balance between ECM synthesis and degradation, through metalloproteinase components of the SASP response.

Senotherapeutic agents are used to target specific properties of cellular senescence; more specifically, senolytics are used to target anti-apoptotic mechanisms and induce cell death within senescent cells. Senolytic drugs may therefore also be potentially used to provide an innovative therapeutic approach to treatment of various conditions. Dasatinib is currently used in the treatment of cancer. It is widely accepted that cancer cells and senescent cells share common anti-apoptotic characteristics, and the combination treatment of dasatinib and quercetin has already been observed to reduce the burden of senescent cells, as well as enhance cardiovascular function, in aged mice. We have reviewed a body of work that, taken together, strongly suggests that senescence could play a significant role in the pathogenesis of OA. Therefore, if dasatinib/quercetin combination therapy is effective in eliminating senescent cells, it could provide an extremely appealing therapeutic target for OA.

Comments

Hi Reason, It seems to me that if anyone would get to the clinic soonest it would be Oisin since it is not using a chemo/drug approach - it is more boolean/conditional ablation based on intracellular expression/markers. Just my guess - YMMV

Posted by: David Gobel at January 31st, 2017 9:20 AM

@David Gobel: My comment was based on an assumption of Oisin taking a more traditional route via trials and regulatory approval.

Posted by: Reason at January 31st, 2017 10:00 AM

right! but this is happening, so...maybe faster?

In meeting with Pharma CEOs, Trump commits to allow treatments/drugs to be available to those who 'will die in 4 weeks", new FDA director who will remove regulatory barriers and streamline FDA to increase innovation. This is clearly bullish for early stage biotech IMO

https://www.youtube.com/watch?v=6RsLpNuFmVE

Posted by: David Gobel at January 31st, 2017 10:09 AM

How is Oisin's gene therapy going to overcome all of the technological obstacles that have bedevilled gene therapy so far? Small molecule drugs from Unity seem far more likely to reach the market in the short term.

I understand that Oisin is not looking to incorporate their gene into the cell's DNA, but that only solves one problem. What about lack of delivery efficiency? Gene silencing? Immunogenicity? The need for broad specificity for the target senescent cells, but a narrow specificity for all other cells in the body? Phagocytosis? Triggering shock? Ensuring its uptake into the correct cellular compartments but not the wrong ones?

Posted by: Jim at February 1st, 2017 4:49 AM

@Antonio - well they just say "The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses."

If it works in vivo and in humans that would be a big advance, and Oisin might be worth a small fortune. So I hope it works.

Posted by: Jim at February 1st, 2017 6:28 AM

@Jim: I would imagine it won't be too long now before Oisin exits the early quiet stage of company development, and more information will become available on their methodology and results to date. There's not much more I can tell you than the contents of that interview, unfortunately.

Posted by: Reason at February 1st, 2017 7:42 AM

@Jim: I can't go into too much detail at this time, but I will say that delivery efficiency is turning out not to be an issue for us, though each tissue necessarily has different transfection efficiency. Immunogenicity has generally not been an issue for neutral liposomes, which we are. We expect to have further immunogenicity data from GLP tox by the end of 2017. Our current tox data is very positive.

As for specificity to senescent cells, the way we target (based on transcription factors) obviates any need for senescent cell targeting using other indicators such as surface markers. Non-p16 cells aren't at all affected, while those with p16 transcription factors are killed very, very efficiently once transduced.

Bottom line for the moment: we see very robust elimination of p16 positive cells by both B-gal staining and PCR, in vivo. I hope to be able to say much more in a few months time.

Posted by: Gary at February 1st, 2017 3:13 PM

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