Granted Patent
B2
US 12,454,706 · App. 18/805,023 · Granted Oct 28, 2025
Methods and compositions for modulating a genome
Inventors:
Anne Helen Bothmer (Cambridge, MA); Cecilia Giovanna Silvia Cotta-Ramusino (Cambridge, MA); William Edward Salomon (West Roxbury, MA); Jacob Rosenblum Rubens (Cambridge, MA); Robert James Citorik (Somerville, MA); Zi Jun Wang (Arlington, MA); Kyusik Kim (Worcester, MA); Randi Michelle Kotlar (Arlington, MA); Ananya Ray (Melrose, MA); Robert Charles Altshuler (Newton, MA); Sandeep Kumar (Newton, MA); Nathaniel Roquet (Philadelphia, PA); Barrett Ethan Steinberg (Somerville, MA)
Assignee:
Flagship Pioneering Innovations VI, LLC
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Abstract
Methods and compositions for modulating a target genome are disclosed. This disclosure relates to novel compositions, systems and methods for altering a genome at one or more locations in a host cell, tissue or subject, in vivo or in vitro. In particular, the invention features compositions, systems and methods for inserting, altering, or deleting sequences of interest in a host genome.
Claims (28)
1. A fusion protein comprising:
a) a reverse transcriptase (RT) domain having the amino acid sequence of SEQ ID NO: 3138,
or a sequence having at least 98% identity thereto; and
b) a Cas9 nickase domain,
wherein the RT domain is C-terminal of the Cas9 nickase domain.
2. The fusion protein of claim 1 , wherein the Cas9 nickase domain is a SpyCas9 nickase domain.
3. The fusion protein of claim 1 , wherein the Cas9 nickase domain is a SpyCas9 (N863A) nickase domain.
4. The fusion protein of claim 1 , wherein the Cas9 nickase domain comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 3269.
5. The fusion protein of claim 1 , wherein the Cas9 nickase domain is an NmeCas9 domain.
6. The fusion protein of claim 1 , wherein the Cas9 nickase domain is an St1Cas9 domain.
7. The fusion protein of claim 1 , wherein the Cas9 nickase domain is a SauCas9 domain.
8. The fusion protein of claim 1 , which further comprises a peptide linker disposed between the RT domain and the Cas9 nickase domain.
9. The fusion protein of claim 8 , wherein the peptide linker is between 2-40 amino acids in length.
10. The fusion protein of claim 1 , which further comprises a nuclear localization sequence (NLS).
11. The fusion protein of claim 10 , wherein the NLS is fused to the N-terminus of the Cas9 nickase domain.
12. The fusion protein of claim 10 , wherein the NLS is fused to the C-terminus of the fusion protein.
13. The fusion protein of claim 10 , wherein the NLS is a monopartite NLS or a bipartite NLS.
14. The fusion protein of claim 10 , which further comprises a linker disposed between the NLS and the Cas9 nickase domain.
15. The fusion protein of claim 1 , wherein the Cas9 nickase domain has an activity at least 50% of that of an otherwise similar Cas9 nickase molecule that is not fused to an RT domain.
16. A nucleic acid encoding the fusion protein of claim 1 .
17. The nucleic acid of claim 16 , which is an mRNA.
18. A system for modifying DNA comprising:
(a) the fusion protein of claim 1 or a nucleic acid encoding the fusion protein; and
(b) a template RNA comprising, from 5′ to 3′ (i) a gRNA spacer that binds a target site, (ii) a sequence that binds the fusion protein, (iii) a heterologous object sequence, and (iv) a 3′ target homology domain.
19. The system of claim 18 , wherein (a) comprises the nucleic acid encoding the fusion protein.
20. The system of claim 19 , wherein the nucleic acid encoding the fusion protein is an mRNA.
21. The system of claim 18 , wherein the sequence that binds the fusion protein is a gRNA scaffold.
22. A lipid nanoparticle (LNP) comprising the system of claim 18 .
Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: RUBENS, JACOB ROSENBLUM; CITORIK, ROBERT JAMES
To: FLAGSHIP PIONEERING, INC.
Reel/Frame 068393/0830 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: KIM, KYUSIK; KOTLAR, RANDI MICHELLE; RAY, ANANYA; ALTSHULER, ROBERT CHARLES; KUMAR, SANDEEP; ROQUET, NATHANIEL; STEINBERG, BARRETT ETHAN
To: TESSERA THERAPEUTICS, INC.
Reel/Frame 068393/0887 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: WANG, ZI JUN
To: TESSERA THERAPEUTICS, INC.
Reel/Frame 068393/0917 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: BOTHMER, ANNE HELEN; COTTA-RAMUSINO, CECILIA GIOVANNA SILVIA; SALOMON, WILLIAM EDWARD
To: TESSERA THERAPEUTICS, INC.
Reel/Frame 068393/0976 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: TESSERA THERAPEUTICS, INC.
To: FLAGSHIP PIONEERING, INC.
Reel/Frame 068394/0062 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 26, 2024
From: FLAGSHIP PIONEERING, INC.
To: FLAGSHIP PIONEERING INNOVATIONS VI, LLC
Reel/Frame 068394/0101 →
Continuity (6)
Continuation
PCTUS2021020948
· Mar 4, 2021
Provisional Application
63067828
· Aug 19, 2020
Provisional Application
63035627
· Jun 5, 2020
Provisional Application
62985285
· Mar 4, 2020
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