This page introduces some of the companies that SRF has empowered to become key players in making the first SENS-derived therapies a reality for patients sooner rather than later.
Cyclarity Therapeutics, Inc., is pursuing a mission to treat the underlying causes of age-related disease. The company develops simple and direct interventions targeting toxic forms of cholesterol using rationally designed molecules to provide the first true diseasemodifying treatments for age-related diseases such as atherosclerosis, hypercholesterolemia, heart failure, and macular degeneration. Its products are based on novel derivatives of a well-known, safe compound and a new way of looking at cardiovascular disease created through a SENS Research Foundation program.
Transthyretin (TTR), a protein involved in the transport of vitamin A and thyroid hormones, is susceptible to becoming a sticky amyloid, which deposits in the joints, carpal tunnels, and most importantly the heart, where it causes senile cardiac amyloidosis (SCA) —a major contributor to heart failure, and the most important contributor to the deaths of supercentenarians.
Catabodies are catalytic antibodies: fragments of IgM antibodies that target aberrant proteins for destruction. Conventional therapeutic antibodies targeting aggregated proteins bind tightly to their target amyloid, with the aim of mobilizing it from the tissue for eventual excretion or degradation. However, this need for conventional antibodies to bind their target for an extended period is inefficient and it may be responsible for the side-effects that have plagued most immunotherapies targeting beta-amyloid in the brain, as the antibody-aggregate complex becomes snared in the blood-brain barrier, leading to damage to brain blood vessels.
Because catabodies catalytically cleave their target instead of binding it, one catabody molecule can cleave multiple aggregate targets before being degraded, and the risk of cerebral vascular side-effects is reduced because antibody-aggregate complexes only exist transiently.
Age-related macular degeneration (ARMD) is the leading cause of blindness in persons over the age of 55 in developed countries. It is caused by the death of photoreceptors in the back of the eye, which in turn is the result of the death and dysfunction of the Retinal Pigmented Epithelium (RPE) cells. RPE are killed or rendered dysfunctional by the accumulation of intracellular aggregates, the most important of which is A2E, a toxic derivative of vitamin A that accumulates in RPE lysosomes.
LYSOCLEAR is a classic application of the LysoSENS strategy of identifying enzymes from microbes and other sources that are capable of degrading a material that the cell is not equipped to handle (in this case A2E and other RPE aggregates), and targeting modified versions of those enzymes to the affected cells, enabling them to eliminate the waste product and return to function.
Some protein-protein interactions that could theoretically be targeted by small molecule drugs as a means of indirectly eliminating aging damage are difficult to target in practice, because the target proteins themselves cannot be manufactured at sufficient purity and scale as to enable high-throughput screening. p53 is a good example, both for cancer and senescent cells: in both cases, the offending cell type is able to survive because p53 is inactivated through interactions with another protein (the Mdm2 oncoprotein and FOXO4, respectively). Drugs that could interrupt these interactions could therefore nudge these age-related aberrant cell types to self-destruct.
Antoxerene’s proprietary RecombiPure expression technology allows them to manufacture full- length, properly-folded, biologically active human p53 and other hard-to-synthesize proteins at scale in E. coli, enabling high-throughput screening of drugs to target them.
The tumor-suppressor gene p53 is the single most frequently mutated gene in human cancer, being involved in roughly 50% of all invasive tumors and in more than 80% of some of the most difficult-to-treat ones. These mutations are considered “undruggable” because most mutations’ contribution to cancer comes from the absence of a functional protein, with no change in the expression of the gene in most cases, so there is an absence of anything with which a drug might interact.
Oisín’s platform technology uses non-integrating genetic “suicide switches” that overcome this problem by providing the cancer cell with a functional p53 promoter, whose activation by the cancer cell’s primed transcription factors acts as the “on switch” that drives the expression of a cellular apoptotic factor such as caspase 8, eliminating the cancerous cell.
The aging body accumulates senescent cells, which exist in a state of growth arrest and secrete a mixture of inflammatory cytokines, proteinases, growth factors, and other factors that is collectively termed the Senescence-Associated Secretory Phenotype (SASP). Extensive evidence links senescent cells to age- related inflammation, cancer, and other diseases of aging — and conversely, studies show that clearing senescent cells from aging tissues delivers sweeping rejuvenating effects in both otherwise-healthy but aging animals and animal models of age-related disease.
“Senolytic” drugs that destroy senescent cells by inhibiting the cell-survival pathways on which senescent cells differentially rely are now close to reaching the clinic. But these drugs have significant limitations: healthy cells also rely on these same pathways for survival in times of crisis, leading to the risk that senolytic agents will destroy hard-to-replace healthy cells along with the senescent ones when those cells are under stress.
Oisín’s platform technology uses non-integrating genetic “suicide switches” that can be induced and withdrawn from the body entirely at will. In this case, the promoter for p16 (a gene expressed in many senescent cells and not normal ones) acts as the “on switch” that drives the expression of a cellular apoptotic factor, leading to the selective destruction of senescent cells.
Repair Biotechnologies is a late preclinical-stage biotech company developing several first-in-class therapies based on the Cholesterol Degrading Platform (CDP).
By safely breaking down excess cholesterol, Repair believes that CDP can repair the failure of reverse cholesterol transport that is at the heart of atherogenesis. Rather than accumulating to make macrophages dysfunctional, excess cholesterol will instead be catabolized.
Adjacent strands of proteins in aging tissues accumulate crosslinks that limit their ability to move independently, leading the tissues to become stiff and lose their elasticity. This contributes to strokes, renal failure, and other end-target pathologies. Cleaving these crosslinks would allow these adjacent strands of protein to move freely again, partially restoring tissue elasticity and reducing these devastating outcomes. Crosslinking by glucosepane — a kind of Advanced Glycation Endproduct (AGE) crosslinking — is thought to be a major contributor to tissue crosslinking with age.
The Yale group behind Revel has developed reagents to enable the development of glucosepane-cleaving agents and its own candidate agents.
Sign up to stay informed about the latest news and opportunities with SRF!
© 2023 SENS Research Foundation – ALL RIGHTS RESERVED