IP Library › Granted Patent US 12,351,815
Granted Patent B2
US 12,351,815 · App. 18/351,689 · Granted Jul 8, 2025

Engineered human-endogenous virus-like particles and methods of use thereof for delivery to cells

Inventors: J. Keith Joung (Winchester, MA); Peter Cabeceiras (Boston, MA)
Assignees: The General Hospital Corporation; President and Fellows of Harvard College
C12N15/86C07K14/005C12N2740/10023C12N2740/10042C12N2740/10052
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Quick Facts
Patent No.
US 12,351,815
App. No.
18/351,689
Granted
Jul 8, 2025
Kind
B2
Abstract

Human-derived virus-like particles (heVLPs), comprising a membrane comprising a phospholipid bilayer with one or more HERV-derived envelope proteins on the external side; one or more HERV-derived GAG proteins in the heVLP core, and a cargo molecule, e.g., a biomolecule and/or chemical cargo molecule, disposed in the core of the heVLP on the inside of the membrane, wherein the heVLP does not comprise a gag protein, except for gag proteins that are encoded in the human genome or gag proteins that are encoded by a consensus sequence that is derived from gag proteins found in the human genome, and methods of use thereof for delivery of the cargo molecule to cells.

Claims (30)

1. A method of engineering a target cell, the method comprising contacting a particle to the target cell, wherein the particle comprises:

(a) a phospholipid bilayer membrane comprising a human endogenous retrovirus (HERV) glycoprotein;

(b) a HERV GAG protein encapsulated within the phospholipid bilayer membrane; and

(c) a therapeutic cargo encapsulated within the phospholipid bilayer membrane, wherein the therapeutic cargo is fused with a plasma membrane recruitment domain, wherein the plasma membrane recruitment domain is not a viral GAG protein or a CD63 protein.

2. The method of claim 1 , wherein the particle does not comprise a non-human gag protein.

3. The method of claim 1 , wherein the particle does not comprise a non-human pol protein.

4. The method of claim 1 , wherein the therapeutic cargo comprises a RNA binding protein or a DNA binding protein.

5. The method of claim 1 , wherein the therapeutic cargo comprises a gene editing reagent.

6. The method of claim 5 , wherein the gene editing reagent comprises a zinc finger (ZF), a transcription activator-like effector (TALE), a CRISPR-based genome editing or modulating protein; or a ribonucleoprotein complex (RNP) comprising the CRISPR-based genome editing or modulating protein.

7. The method of claim 5 , wherein the gene editing reagent comprises an RNA guided protein.

8. The method of claim 5 , wherein the gene editing reagent further comprises a guide RNA.

9. The method of claim 1 , wherein the HERV glycoprotein is fused to a targeting polypeptide.

10. The method of claim 9 , wherein the targeting polypeptide comprises a single-chain variable fragment (ScFv).

11. The method of claim 1 , wherein the plasma membrane recruitment domain is a human endogenous gag protein.

12. The method of claim 11 , wherein the human endogenous gag protein is a HERV GAG protein.

13. The method of claim 11 , wherein the human endogenous gag protein comprises a HERV GAG consensus sequence.

14. The method of claim 1 , wherein the plasma membrane recruitment domain is a human plasma membrane recruitment domain.

15. The method of claim 1 , wherein the plasma membrane recruitment domain comprises a pleckstrin homology (PH) domain.

16. The method of claim 15 , wherein the PH domain is selected from the group consisting of a Pleckstrin homology domain of phospholipase Cδ1 (PLCδ1), Pleckstrin homology domain of Akt1 or a mutant thereof, and Pleckstrin homology domain of PDPK1.

17. The method of claim 15 , wherein the PH domain is a mutant pleckstrin homology domain of Akt1 that comprises an amino acid substitution relative to a corresponding wild type Pleckstrin homology domain of Akt1.

18. The method of claim 17 , wherein the amino acid substitution comprises an amino acid substitution of amino acid residue E17 relative to the corresponding wild type pleckstrin homology domain of Akt1.

19. The method of claim 17 , wherein the amino acid substitution is E17K.

20. The method of claim 1 , wherein the plasma membrane recruitment domain comprises the amino acid sequence selected from the group consisting of the amino acid sequence of any one of SEQ ID NO: 19, 24-27, and 29-32.

21. The method of claim 1 , wherein the HERV GAG protein comprises a GAG protein sequence of HERV-K113, HERV-K101, HERV-K102, HERV-K104, HERV-K107, HERV-K108, HERV-K109, HERV-K115, HERV-K11p22, or HERV-K12q13.

22. The method of claim 1 , wherein the HERV GAG protein comprises a HERV GAG consensus sequence.

23. The method of claim 22 , wherein the HERV GAG consensus sequence gag protein comprises is encoded by the amino acid sequence of SEQ ID NO: 19.

24. The method of claim 1 , wherein the HERV glycoprotein is selected from the group consisting of: hENVH1, hENVH2, hENVH3, hENVK1, hENVK2, hENVK3, hENVK4, hENVK5, hENVK6, hENVT, hENVW, hENVFRD, hENVR, hENVR(b), hENVF(c)2, hENVF(c)1, and hENVKcon glycoprotein.

25. The method of claim 1 , wherein the HERV glycoprotein comprises the amino acid sequence of any one of SEQ ID NOs: 2-18.

26. The method of claim 1 , wherein the target cell is in vitro.

27. The method of claim 1 , wherein the target cell is in vivo.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2023
From: THE GENERAL HOSPITAL CORPORATION
To: THE GENERAL HOSPITAL CORPORATION; PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 064401/0649 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2023
From: JOUNG, J. KEITH; CABECEIRAS, PETER
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 064401/0739 →
Continuity (3)
Continuation 17617490
Provisional Application 62861186 · Jun 13, 2019
Related Publication 20240011050A1 · Jan 11, 2024
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