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More Evidence for Senescent Cells as a Significant Cause of Osteoarthritis

UNITY Biotechnology has obtained a large amount of venture funding in order to work on senolytic therapies, treatments capable of removing significant numbers of the senescent cells that accumulate with advancing age. Cellular senescence is one of the root cases of aging, as these cells cause inflammation and disruption of tissue structure and function. Enough of them can and will kill you, though the usual mechanism of producing ultimately fatal age-related diseases, assuming that none of the other causes of aging get there first. The UNITY Biotechnology principals initially aim to push senolytics through the regulatory process as a treatment for degenerative joint conditions such as osteoarthritis, though in reality removal of senescent cells is a general purpose rejuvenation therapy that everyone should undergo every few years, and as such should be expected to impact most age-related conditions. Regulators are not in favor of treatments for aging, however, so efforts become channeled into becoming narrowly approved, late stage interventions. The true and most beneficial use will happen unofficially, or via medical tourism.

Since there is now a great deal of money and interest in this field, and since osteoathritis is an early target for UNITY Biotechnology, a fair number of interesting papers on this topic have emerged in recent months, providing ever more evidence for senescent cells in joint tissues to be a direct cause of degeneration. The latest paper quoted below is more of the same, and I think the point has been well made by now. The next thing to look for is proof of principle in early human tests. If they follow the pattern established in animal models, determination of effectiveness and reliability should follow on fairly rapidly from the treatment, perhaps a matter of a few weeks or months at the outside. This, of course, is a good reason to start with joint diseases, if you have to focus on any one class of conditions. Results are more easily assessed.

UNITY Biotechnology is expected to kick off human trials at some point this year, and it appears that at least at the outset they are working with navitoclax, or ABT-263. Confusingly, they use their own company code for the compound here, UBX0101; you'd have to read the full paper to see that it refers to navitoclax. Unfortunately it isn't open access. I have to think, and have said as much recently, that UNITY Biotechnology is not going to follow all the way through with navitoclax, though they may well use it for their first trials. It has the advantage of being well characterized as a drug, but beyond that it is somewhat worse than many of the other approaches to clearing senescent cells. For one, it is a chemotherapeutic with significant side-effects, and to pick two examples, both the Oisin Biotechnologies gene therapy and the new FOXO4-p53 therapy are not expected to produce notable side-effects while clearing senescent cells. So I believe that the UNITY Biotechnology researchers will switch horses at some point.

Nature Medicine Study Describes a Novel Senolytic Molecule that Slows the Progression of Osteoarthritis

UNITY Biotechnology, Inc. announced today the publication of new research demonstrating that the selective elimination of senescent cells with a drug may delay, prevent, or even reverse the progression of osteoarthritis (OA), the age-associated inflammatory condition causing chronic joint pain in 80% of people over 65. Researchers found that senescent cells accumulate in the knees of mice, and that the selective elimination of these senescent cells using UBX0101 - UNITY's first-in-class senolytic molecule - slowed the progression of disease, reduced pain, and induced cartilage production in human knee tissue grown in culture.

"For decades, OA has been thought of as a chronic inflammatory disease. The big mystery in OA was where the inflammatory molecules were coming from. Our new work answers this question, at least in part. It appears that the inflammatory factors that drive OA are made by senescent cells. You eliminate senescent cells, and you stop OA. This is a unique approach to the treatment of osteoarthritis and if it can be translated into a therapeutic approach for human OA, it could result in a major change in the way we treat the disease."

Osteoarthritis was induced in both young and old mice by using a standard ACL transection (ACLT) model. The resulting mechanical instability of the joint drives the accumulation of senescent cells in the articular cartilage and synovial membranes of the knees. The senescent cells appear within weeks of ACL transection and symptoms of OA are evident at 30 days. A similar accumulation of senescent cells occurs naturally over time as mice age, resulting in cartilage destruction without any surgical intervention. In mice, elimination of senescent cells from 12 months onwards maintains youthful cartilage, even in animals as old as 28 months (equivalent to approximately 80 years old for people). Following clearance of senescent cells with UBX0101 in the ACLT model, both OA-related pain and cartilage erosion were reduced, and cartilage began to regenerate. In cartilage grown from human knees with advanced OA, UBX0101 selectively eliminated senescent cells, increased proliferation of healthy chondrocytes, and induced new cartilage growth.

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown.

To test the idea that SnCs might play a causative role in OA, we used a transgenic mouse model that allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

Comments

Why would they bother to start testing a molecule they do not intend to take right through to approval? I think Unity are just hoping that the side effects are manageable and that they can get to market quickly as this molecule is already approved for other indications.

Oisin's gene therapy probably faces a much longer road with regulators.

Posted by: Jim at April 25th, 2017 11:29 PM

I was also confused with UBX0101, but I was informed by Nathaniel David of Unity that it is not ABT-263. They will not be publishing the structure.

Posted by: DGAB at April 26th, 2017 1:02 PM

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