Ichor Therapeutics’ LysoClear
When cells detect that they have been irreversibly damaged, they enter a non-dividing condition known as cell-cycle arrest, or senescence. It’s believed this occurs to prevent cells from going rogue and turning cancerous. Ideally, they should die by the process known as apoptosis, but as we age, more and more frequently they don’t. They become zombie cells – unable to kill themselves or resume normal function.
Senescent cells secrete molecules that cause inflammation in an effort to attract immune cells that would usually clear them. But for reasons that are not fully known, as we age, persistently senescent cells accumulate, leading to a vast number of age-related diseases.
Oisín is developing a highly precise, patent-pending, DNA-targeted intervention to clear these cells. As a recent study has shown, clearing senescent cells both reduces negative effects of aging pathologies and also extends median lifespan and survival.
Oisin Accomplishments to Date and the Future
There are two major challenges to clearing senescent cells using our approach.
First is to design and create the DNA construct that recognizes that a cell has become senescent, and then destroys it.
Second is to safely and efficiently deliver this construct into cells throughout the body.
Both goals have been achieved in our pioneering proof of concept experiments in 2016.
Oisin first demonstrated the ability to transduce cells both in vitro (cell culture) and in vivo (in aged mice). Then we showed that p16 positive senescent cells can be killed on demand in both in vitro and in vivo environments. Now they are embarked on experiments that will show improvements in both healthspan and lifespan in model organisms from mice to primates. And then, everything changes.
*SENSOlytics™ is an Oisín proprietary platform technology that enables precise targeting of a senescent cell based on the DNA expression of the cell, not on surface markers or other characteristics that might be shared with normal, undamaged cells.
Oisin Biotechnologies differs from other companies producing senolytic therapies, the name given to treatments that destroy>A senescent cells, in one very important way. The Oisin technology is highly adaptable, and can be programmed to kill any class of cell that has some distinct internal marker in the form of high levels of expression of a specific protein. The founders started with senescent cells based on the p16 marker, but as this latest interview with Gary Hudson makes clear, have expanded their efforts to effectively target cancer with p53, and beyond that they are really only limited by time, funding, and a good map of the internal biochemistry of the target cell type. The sky is the limit in the long term: any type of cell that is undesirable should have some distinctive chemistry that can be attacked, and there are many possible targets.
In June and August of 2016 they demonstrated that naturally-aged, 80-week-old B6 mice, could be safely treated with our therapeutic and have their senescent cells (SCs) reduced significantly in a dose-dependent fashion. For example, a single treatment reduced senescence-associated β-galactosidase (β-gal) staining (a well-accepted marker for senescence) by more than 50% in the kidneys, and restored the tissue appearance to that of about 18-week-old animals. This reduction in SCs was also confirmed by DNA PCR analysis.
They tested their therapeutic in oncology applications. They targeted tumors with p53, in place of the p16 targeting they use in their anti-aging applications. They saw as much as 90% reductions in tumor mass in 24-48 hours of treatment. These results were astonishing and virtually unprecedented.
They subsequently repeated these studies in immunocompetent mice intravenously infused with the aggressive B16 melanoma cell line and showed a reduction in lung tumor metastases of nearly twenty-fold over controls.
The Oisin technology uses two elements.
1. They design a DNA construct that contains the promoter we wish to target. This promoter controls an inducible suicide gene, also called iCasp9 (no relation to CRISPR’s Cas9).
2. They encapsulate that DNA in a specialized type of liposome known as a fusogenic lipid nanoparticle (LNP). The LNP protects the DNA plasmid during transit through the body’s vasculature, and enables rapid fusion of the LNP with cell membranes. This LNP vector is consider “promiscuous” as it has no particular preference for senescent cells – it will target almost any cell type. Once it does, the DNA plasmid is deposited into the cytoplasm and traffics to the nucleus. There it remains dormant unless the cell has transcription factors active that will bind to our promoter. If that happens, then the inducible iCasp9 is made. The iCasp9 doesn’t activate unless a small molecule dimerizer is injected; the dimerizer causes the iCasp9 protein halves to bind together, immediately triggering apoptosis. This process insures that the target cells and bystander cells are left unharmed.
So far, they have not observed any off-target effects.
They also have tweaks to both the promoter side and the effector side of the constructs that will provide even more interesting and useful extensions to the basic capability.