Methods of using ZSCAN4 for rejuvenating human cells
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Publication Number
US-10335456-B2
Publication Date
2019-07-02
Expiration Date
Abstract
The present disclosure relates to methods for increasing telomere length in one or more human cells and/or increasing genome stability of one or more human cells, for example by contacting one or more human cells with an agent that increases expression of Zscan4 in the one or more human cells. Methods of treating a subject in need of telomere lengthening, treating a disease or condition associated with a genomic and/or chromosome abnormality, of rejuvenating one or more human cells, of rejuvenating tissues or organs, and of rejuvenating a subject in need thereof, for example by contacting one or more human cells in the subject with an agent that increases expression of Zscan4, or by administering to a subject in need thereof, an agent that increases expression of Zscan4 are also provided.
Core Innovation
The invention relates to methods to treat human subjects and/or human cells by increasing Zscan4 expression or providing an isolated nucleic acid encoding Zscan4 or providing a Zscan4 protein, wherein Zscan4 induces extension of telomeres. The disclosed approach is presented as correcting cellular defects associated with telomere shortening, with improved genome stability and DNA repair capacity, and correction of chromosome/karyotype abnormalities.
The problem addressed is bone marrow failure caused by telomere shortening, including bone marrow failure associated with Fanconi anemia, dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome. The document also describes an unmet need for correcting telomere-related cellular dysfunction and abnormal chromosome populations, including trisomy 21 and aneuploidy, in human cell populations.
In particular, the disclosure states that human ZSCAN4 expression in adult human fibroblasts rapidly increases telomere length and that this can lead to improved genome stability and DNA repair capacity. The document also describes use of Zscan4 protein embodiments and nucleic-acid formats as means to deliver Zscan4 to human cells, including bone marrow or blood cells.
The invention is further described as applicable to additional human contexts, including IVF success and correction of aneuploidy in oocytes/embryos, and topical skin and hair indications. The document also presents cancer-related approaches using Zscan4-mediated effects, including a contrast that reduces endogenous ZSCAN4 in cancer stem cells to improve chemotherapy responsiveness, and describes resistance to genotoxic agents in the context of Zscan4-mediated telomere and genome maintenance.
Claims Coverage
The independent claim coverage centers on a two-stage therapeutic method with Zscan4-mediated telomere extension followed by engraftment, comprising 1) contacting human bone marrow or blood cells with an isolated nucleic acid encoding Zscan4 or a Zscan4 protein, and 2) engrafting the contacted cells to ameliorate telomere-shortening-caused bone marrow failure. Dependent claims add synthetic mRNA, Sendai virus vector delivery context, Zscan4-ERT2 or Zscan4-ΔC variants, and optional fusion to a cell-penetrating peptide.
Zscan4-induced telomere extension in human bone marrow or blood cells
Contacting one or more human bone marrow or blood cells with an isolated nucleic acid molecule encoding Zscan4 or a Zscan4 protein, wherein the isolated nucleic acid molecule encoding the Zscan4 or the Zscan4 protein induces extension of telomeres in the one or more human bone marrow or blood cells.
Engrafting Zscan4-contacted cells to treat telomere-shortening-caused bone marrow failure
Engrafting the contacted one or more human bone marrow or blood cells into the subject to treat the bone marrow failure associated with Fanconi anemia, dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome, wherein the bone marrow failure is caused by telomere shortening, and wherein the associated bone marrow failure is ameliorated.
Synthetic mRNA encoding Zscan4
The isolated nucleic acid molecule is a synthetic mRNA.
Sendai virus vector delivery context
The vector is a Sendai virus vector.
Zscan4-ERT2 or Zscan4-ΔC as the Zscan4 variant
The method is performed using either a Zscan4-ERT2 fusion protein or a Zscan4-ΔC protein as the Zscan4 variant.
Fusing Zscan4 protein to a cell-penetrating peptide
The Zscan4 protein is fused to a cell-penetrating peptide.
Overall, the claims coverage centers on Zscan4-mediated induction of telomere extension in human bone marrow or blood cells followed by engraftment to ameliorate bone marrow failure caused by telomere shortening associated with Fanconi anemia, dyskeratosis congenita, or Hoyeraal-Hreidarsson syndrome, with dependent refinements specifying synthetic mRNA, Sendai vector context, particular Zscan4 variants, and optional fusion of Zscan4 to a cell-penetrating peptide.
Stated Advantages
Induces extension of telomeres in the contacted one or more human bone marrow or blood cells.
Ameliorates bone marrow failure associated with Fanconi anemia, dyskeratosis congenita, or Hoyeraal-Hreidarsson syndrome caused by telomere shortening.
Improved genome stability and DNA repair capacity.
Correction of chromosome/karyotype abnormalities.
Rapidly increases telomere length in adult human fibroblasts.
Documented Applications
Treating bone marrow failure associated with Fanconi anemia, dyskeratosis congenita, or Hoyeraal-Hreidarsson syndrome in a subject by contacting human bone marrow or blood cells with Zscan4-encoding nucleic acid or Zscan4 protein and engrafting the contacted cells.
Correcting telomere-related cellular dysfunction and abnormal chromosome populations, including trisomy 21 and aneuploidy, in human cell populations.
IVF success and correction of aneuploidy in oocytes/embryos.
Topical skin and hair indications.
Cancer-related approaches using Zscan4-mediated effects, including improving chemotherapy responsiveness.
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