- Elimination of pro-inflammatory senescent cells, or down-regulation of their pro-inflammatory senescence-associated secretory phenotype (“SASP”) have both been shown to reverse the phenotypic effects of aging.
- Two distinct senolytic approaches and one senomorphic approach are being pursued to eliminate senescent epithelial and mesenchymal cells, associated with pre-cancerous, aging-related lesions or reduce their negative inflammatory SASP:
- Topical skin or systemic administration of a proprietary senolytic peptide, PTC-2101 (YuuthTM), to directly reduce the burden of senescent cells in the skin and throughout the organs of the body.
- Expression of a rimiducid-sensitive allele of the pro-apoptotic protein, Caspase-9 (ApoptiCIDeTM) targeted to senescent cells using our proprietary chimeric p16- and/or UPAR-based promoters, with administration of our proprietary rimiducid IM formulation, PTC-1102, to trigger their elimination as senolytic therapy.
- Proprietary selective JAK2, JAK2/3 or JAK3/TYK2 tyrosine kinase inhibitors (“TKI”) applied topically as senomorphic therapy to severely UV-damaged skin to reverse the deleterious effects caused by the aging- and sun damage-related accumulation of senescent cells.
Senescent Cells: A Validated Anti-Aging Target
- Cellular senescence is characterized by irreversible cell cycle arrest and a proinflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases
- Senescent cells accumulate during aging and negatively influence lifespan and promote age-dependent changes in several organs
- Clearance of senescent cells has been shown to improve function in organs of the body in mouse models
- Therapeutic removal of senescent cells is an attractive approach to extend healthy lifespan.
- β-galactosidase (β-gal) (blue) staining is a commonly used method to identify senescent cells in tissue samples
- Allows researchers to easily identify and quantify senescent cells in tissues and organs of the body
- We are developing PTC-2101 (“Yuuth”), administered either topically on the skin or systemically, as a senolytic therapeutic, to directly reduce the burden of senescent cells in the skin and throughout the organs of the body.
Regulating the Senescence-
Associated Secretory Phenotype (SASP)
- Cellular senescence is characterized by irreversible cell cycle arrest and a proinflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases.
- Senescent cells accumulate during aging and negatively influence lifespan and promote age-dependent changes in several organs.
- IL-1, IL-6, IL-8, TNF-α, TGF-β, and various matrix metalloproteinases (MMP3, 12) make up the key components of the SASP. The sustained inflammatory microenvironment created by the SASP can lead to chronic inflammation, which can have detrimental affects on tissues and organs, contributing to various age-related diseases and conditions.
- JAK kinases regulate the SASP through the JAK/STAT pathway.
- We are developing selective JAK2/3 topical TKIs as senomorphic therapy to down-regulate the SASP without the potential negative adverse effects of JAK1 inhibition.
iCaspase-9/ApoptiCIDeTM
Mechanism:
Ligand-controlled dimerization of Caspase-9 triggers to its full activation, leading to activation of downstream effector caspases, Caspase-3, -6, and -7) and non-inflammatory apoptosis.
This is a non-immunogenic, low basal activity, cell cycle-independent method of initiating apoptosis and relies on a clinically validated and safe activating ligand
Microneedle Delivery
Mechanism:
There are many options for transdermal DNA delivery, including intradermal injection, electroporation, Gene Gun biolistic particle delivery, and microneedles (MNs), which come in several different forms, such as microchannels, coated, and dissolving MNs, (comprising biodegradable polymers). We plan to use dissolving MNs, due to higher loading payload capacity and ease of use. Although we plan to apply it over a relatively small area, others have shown the practicality and safety of application to a much larger area, including the face in cosmetic applications (before/after shown).
As a lead option, we will load NPs with mini-plasmid along with a tissue permeability-enhancing peptide (PEP) ± transposase mRNA and embed it in a biodegradable Polyvinyl alcohol (PVA) MN mold (shown).
Senescence-Restricted Apoptosis Switch
Mechanism:
Activation of the senescence-dependent promoter leads to restricted expression of the pro-apoptotic Rejuvenation Switch in senescent cells. Subsequent administration of the activating ligand triggers safe elimination of these targeted skin-associated senescent cells, releasing stem cell niches from pathological inhibition and resulting in restoration of normal skin rejuvenation and barrier function.
The plasmid backbone can be greatly reduced in size to eliminate antibiotic resistance genes and extraneous foreign DNA to improve expression and facilitate regulatory approval. Alternatively, the therapeutic gene cassette will be stably integrated into the genome using transposon technology, eliminating the bacterial sequence altogether.
Senescence-Restricted Apoptosis-Method 2
Mechanism:
Expression of the senolytic peptide within the skin lesion causes apoptosis of senescent cells while leaving unharmed cycling cells and normal stem and precursor cells.
Inclusion of a Scaffold/(Nuclear) Matrix-Attachment Region (S/MAR) ensures prolonged long-term expression of the senolytic peptide.