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WO-2026096751-A1 - NON-VIRAL GENE DELIVERY SYSTEM COMPOSITIONS

WO2026096751A1WO 2026096751 A1WO2026096751 A1WO 2026096751A1WO-2026096751-A1

Abstract

The present invention generally relates at least in part to compositions comprising non-viral vector gene therapies that can provide a means of enhancing rate and efficiency of transport to the nucleus. Also provided herein at least in part are non-virally delivered DNA compositions that exhibit nuclear transport and can be used for the treatment of a broad range of pathologies.

Inventors

  • HOLLANDER, Judith
  • ALTUG, Yasemin
  • GORALTCHOUK, ALEXEI
  • Luppino, Frank
  • SEREGIN, Alexey

Assignees

  • Remedium Bio, Inc.

Dates

Publication Date
20260507
Application Date
20251030
Priority Date
20241030

Claims (20)

  1. CLAIMS
  2. What is claimed is:
  3. 1. A therapeutic non-viral gene delivery system for the treatment of human or veterinary pathologies comprised of:
  4. A. one or more DNA cassettes encoding one or more therapeutic transgenes or therapeutic non-coding DNA regions, and one or more protein binding stretches of DNA,
  5. B. one or more non-covalently attached peptides or hybrid peptides comprised of a nuclear localization sequence, spacer, and a DNA binding stretch of amino acid, which binds to one or more of the proteinbinding stretches from the DNA cassette.
  6. C. With an overall composition such that the stoichiometric ratio of protein binding sites to peptide molecules per non-viral gene delivery particle exceeds a critical pairing number.
  7. 2. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of KRGRKP.
  8. 3. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of IRKKRGRKPLPPEQKAARRPV.
  9. 4. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of a DEXX motif.
  10. 5. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of a DEAH, DEAD, or DECH, sequence. 6. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of LXXLL motifs such as LHTLL, LHKLL, or LRYLL.
  11. 7. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of known motifs with stretches of basic amino acids.
  12. 8. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of KRFARADKRGKLPR, KIEPSKPTATRKRRWSAPETRKLEKSEDEPPLTLPKPSL, PKGRQRK, or KPRRIRKPR.
  13. 9. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of a general monopartite sequence, such as K (K/R) X (K/R).
  14. 10. Nuclear localization sequence in Claim 1, which includes the motif K (K/R) X (K/R).
  15. 11. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of a general bipartite sequence, such as R/K (X) 10-12KRXK.
  16. 12. A nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of RRTIRLKLI YDRCDLNCRIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKEK LLAE.
  17. 13. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of EYQSAIKVEPASPP YYSEKTQLYNRPHEEPSNSLMAI.
  18. 14. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of PAAKRVKLD.
  19. 15. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of SQKHLQINQTFEELRLVT.
  20. 16. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of DEXX. Nuclear localization sequence in Claim 1, which is comprised at least in part from at least a part of LXXLL.

Description

NON— VIRAL GENE DELIVERY SYSTEM COMPOSITIONS RELATED APPLICATIONS This application claims the benefit of priority under 35 U. S. C. § 119 (e) of U. S. Provisional Application Serial No. 63/713, 615, filed on October 30, 2024, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention generally relates at least in part to compositions comprising non-viral vector gene therapies that can provide a means of enhancing rate and efficiency of transport to the nucleus. Also provided herein at least in part are non-virally delivered DNA compositions that exhibit nuclear transport and can be used for the treatment of a broad range of pathologies. SUMMARY OF THE INVENTION Gene therapy is a major therapeutic modality that can enable curative treatment of a broad range of conditions by replacing or augmenting genes, or enabling the production of therapeutic proteins directly inside the body. In a DNA gene therapy, generally, the genetic cargo is delivered using a vector that enables transport of the nucleic acid to the nucleus, where it can be transcribed for downstream therapeutic activity. Most clinical trials and approved products have delivered DNA using viral vectors such as adeno associated virus, herpes simplex virus, adenovirus, and lentivirus; such vectors can be effective at ensuring the therapeutic DNA ends up in the nucleus of the cell being treated or the cell producing the therapeutic protein. However, although traditional viral vector gene therapies have seen a number of successes in clinical studies, they are expensive, antigenic, and not dose-adjustable. Non-viral vectors have a number of advantages over viral vectors including cost, non-antigenicity, potential for dose adjustability, and the ability to deliver a large genetic cassette size. However, DNA cassettes delivered to the cytoplasm by non-viral vectors can be rate- and size-limited in their transport to the nucleus. Thus, provided herein are compositions and methods that can address the foregoing issues. The present invention provides at least in part means of enhancing rate and efficiency of nuclear transport of non-virally delivered DNA. The compositions and methods provided herein can be used for the treatment of mammalian and animal pathologies. In an aspect is a therapeutic non-viral gene delivery system for the treatment of human or veterinary pathologies comprised of: A. one or more DNA cassettes encoding one or more therapeutic transgenes or therapeutic non-coding DNA regions, and one or more protein binding stretches of DNA, B. one or more non-covalently attached peptides or hybrid peptides comprised of a nuclear localization sequence, spacer, and a DNA binding stretch of amino acid, which binds to one or more of the proteinbinding stretches from the DNA cassette, and C. with an overall composition such that the stoichiometric ratio of protein binding sites to peptide molecules per non-viral gene delivery particle exceeds a critical pairing number. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part from at least a part of KRGRKP. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of IRKKRGRKPLPPEQKAARRPV. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of a DEXX motif. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of a DEAH, DEAD, or DECH, sequence. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of LXXLL motifs such as LHTLL, LHKLL, or LRYLL. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of known motifs with stretches of basic amino acids. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of KRFARADKRGKLPR, KIEPSKPTATRKRRWSAPETRKLEKSEDEPPLTLPKPSL, PKGRQRK, or KPRRIRKPR. In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of a general monopartite sequence, such as K (K/R) X (K/R). In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence includes the motif K (K/R) X (K/R). In one embodiment of any one of the compositions or methods provided herein, the nuclear localization sequence is comprised at least in part of at least a part of a general bipartite sequence, such as R