Therapeutic applications of p53 isoforms in regenerative medicine, aging and cancer
Inventors
Harris, Curtis C. • Fujita, Kaori • Horikawa, Izumi • Vojtesek, Borivoj • Bourdon, Jean-Christophe • Lane, David P.
Assignees
Masaryk Memorial Cancer Institute • University of Dundee • US Department of Health and Human Services
Publication Number
US-9944927-B2
Publication Date
2018-04-17
Expiration Date
2028-10-21
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Abstract
The present invention provides methods and compositions for modulating cell senescence and cell proliferation using isoforms of the p53 tumor suppressor protein. The methods and compositions of the invention find use in inhibiting cancer cell growth or in generating populations of cells for tissue regeneration through the modulation of cell senescence and proliferation.
Core Innovation
The invention provides methods and compositions for modulating cell senescence and cell proliferation by utilizing isoforms of the p53 tumor suppressor protein, specifically Δ133p53 and p53β. Δ133p53 inhibits cellular senescence and promotes cell proliferation, whereas p53β induces cellular senescence. The modulation of these isoforms allows manipulation of cancer cell growth and the generation of cells for tissue regeneration.
The problem addressed arises from cellular senescence, a state of irreversible growth arrest limiting the replicative lifespan of normal human cells, which impacts aging, cancer, and tissue regeneration. Cellular senescence is regulated by mechanisms involving the tumor suppressor p53 through telomere shortening, derepression of the INK4a/ARF locus, and DNA damage. However, regulation mechanisms of p53 isoforms in senescence processes were not well understood prior to this invention.
The invention discovers a novel telomere-mediated mechanism by which p53 activity is regulated through its natural isoforms. Specifically, switching expression from Δ133p53 to p53β results in replicative cellular senescence. Δ133p53 represses p53 transcriptional targets such as p21WAF1 and miR-34a, and inhibits p53-mediated degradation of TRF2, allowing cells to bypass normal senescence checkpoints and extend replicative lifespan. The invention leverages this insight to modulate senescence and proliferation for therapeutic uses.
Claims Coverage
The claims include three independent claims focusing on methods for modulating immune cell function via manipulation of Δ133p53 expression in T cells using polynucleotides.
Enhancement of immune cell function by activating Δ133p53 expression
A method of enhancing immune cell function in a population of T cells containing endogenous wild-type p53 by introducing an agent that activates the function or expression of Δ133p53, wherein the agent comprises a polynucleotide encoding Δ133p53 or an expression cassette encoding Δ133p53.
Application to mammalian and human T cell populations
The method is applicable to mammalian T cell populations, including specifically human T cell populations.
Application to CD8+ T cells
The method is applicable to populations of T cells comprising CD8+ T cells.
The independent claims cover methods of enhancing immune function of T cell populations by using agents, particularly nucleic acid-based agents, that activate Δ133p53 expression or function, with specific applicability to mammalian, human, and CD8+ T cells.
Stated Advantages
The modulation of p53 isoforms allows manipulation of cellular senescence and proliferation.
Inhibiting Δ133p53 promotes senescence and inhibits cancer cell growth.
Activating Δ133p53 inhibits senescence and extends replicative lifespan, useful for tissue regeneration and anti-aging.
Targeted manipulation of p53 isoforms can treat degenerative diseases and cancers by regulating cell proliferation and senescence.
The use of isoform-specific agents enables selective regulation without affecting other p53 isoforms.
Documented Applications
Inhibition of Δ133p53 for promoting cell senescence and inhibiting cancer cell growth.
Activation of Δ133p53 to extend replicative lifespan of cells and generate populations for tissue regeneration.
Inhibition or activation of p53β respectively to promote or inhibit senescence for cancer treatment or regeneration.
Inhibition of miR-34a to extend replicative lifespan and enhance immune functions.
Enhancement or restoration of immune functions by extending T cell lifespan through modulation of Δ133p53, p53β, or miR-34a.
Generating cell populations suitable for tissue regeneration by modulating p53 isoforms.
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