Granted Patent
B2
US 12,435,359 · App. 17/457,572 · Granted Oct 7, 2025
Fractional initiator hybridization chain reaction
Assignee:
California Institute of Technology
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Abstract
The present disclosure relates to methods and compositions involving HCR reactions that involve initiators that are split into two or more parts. Effective HCR is dependent upon two or more of these split initiators being brought into proximity (e.g., via binding events mediated by a target) such that a full initiator is formed that is capable of triggering HCR signal amplification.
Claims (74)
1. A composition, comprising:
a target molecule,
a first fractional initiator probe comprising:
a first target binding region and a first fractional initiator,
a second fractional initiator probe comprising:
a second target binding region and a second fractional initiator,
and a first hairpin monomer comprising:
a first input domain comprising a first toehold and a first stem section, and a first output domain comprising a first loop and a complement to the first stem section;
wherein the first and second target binding regions are capable of binding the target molecule so as to colocalize the first and second fractional initiators, and
wherein the colocalized first and second fractional initiators are capable of binding to the first input domain of the first hairpin monomer to open the first hairpin monomer and expose the first output domain.
2. The composition of claim 1 further comprising:
a second hairpin monomer comprising:
a second input domain comprising a second toehold and a second stem section, and
a second output domain comprising a second loop and a complement to the second stem section;
wherein the exposed first output domain is capable of binding to the second input domain to open the second hairpin monomer and expose the second output domain.
3. A method comprising:
providing:
a target molecule,
a first fractional initiator probe comprising:
a first target binding region and a first fractional initiator,
a second fractional initiator probe comprising:
a second target binding region and a second fractional initiator, and
a first hairpin monomer comprising:
a first input domain comprising a first toehold and a first stem section, and a first output domain comprising a first loop and a complement to the first stem section;
incubating to allow for binding, wherein the first and second target binding regions bind the target molecule, colocalizing the first and second fractional initiators, and wherein the colocalized first and second fractional initiators bind the first input domain of the first hairpin monomer to open the first hairpin monomer and expose the first output domain; and
detecting a signal.
4. The method of claim 3 further comprising:
a second hairpin monomer comprising:
a second input domain comprising a second toehold and a second stem section, and
a second output domain comprising a second loop and a complement to the second stem section;
wherein the exposed first output domain binds to the second input domain to open the second hairpin monomer and expose the second output domain.
5. A method of performing HCR, the method comprising:
adding a first fractional initiator and a second fractional initiator to a sample, wherein together the first and the second fractional initiators provide a full HCR initiator; and
adding a set of HCR hairpin monomers to the sample to allow HCR to occur in the presence of the full HCR initiator.
6. The method of claim 5 , wherein the first fractional initiator is part of a first fractional initiator probe and wherein the second fractional initiator is part of a second fractional initiator probe.
7. The method of claim 5 , wherein the method is part of an in situ process to image DNA, RNA, protein, or small molecule targets selected from the group consisting of DNA in situ hybridization (ISH), RNA in situ hybridization (ISH) and protein immunohistochemistry (IHC).
8. The method of claim 5 , wherein the method comprises a 2-stage approach with a wash after each stage, and wherein a target is immobilized, and wherein the sample is fixed.
9. The method of claim 8 , wherein a first stage is a detection stage that comprises binding probes to the target and washing away unbound probe, and wherein a second stage is an amplification stage, wherein HCR amplification occurs, followed by washing away unpolymerized hairpin monomers.
10. The method of claim 5 , wherein the method is applied in vitro and wherein the target is immobilized on a bead or microarray.
11. The method of claim 5 , wherein the method is in vitro or in vivo and wherein the target is not immobilized.
12. The method of claim 5 , wherein the method comprises a single stage protocol with no washes.
13. The method of claim 5 , wherein the target is at least one of DNA, RNA, protein, or small molecule target molecules or complexes in vitro, in situ, or in vivo.
14. The method of claim 5 , wherein the first fractional initiator is part of a first fractional initiator probe that further comprises a first target binding section.
15. The method of claim 14 , wherein the second fractional initiator is part of a second fractional initiator probe that further comprises a second target binding section.
16. The method of claim 14 , wherein the first target binding section is configured to bind adjacent to the second target binding section when the first fractional initiator probe and the second fractional initiator probe are both bound specifically to the target.
17. The method of claim 5 , wherein each of the set of HCR hairpin monomers comprises a reporter molecule.
18. The method of claim 17 , wherein the reporter molecule is a fluorescent molecule.
19. The method of claim 18 , wherein the reporter molecule comprises a quenched or FRET arrangement, wherein the fluorescent molecule on the set of HCR hairpin monomers is dequenched when a polymer configuration is achieved by the set of HCR hairpin monomers.
20. The method of claim 5 , wherein the set of hairpin monomers form a FRET pair when combined as a polymer.
21. The method of claim 20 , wherein the FRET pair is formed due to a change in quenching or FRET that occurs when the hairpin monomers open and polymerize.
22. The method of claim 17 , wherein the reporter molecule is a non-fluorescent reporter molecule.
23. The method of claim 17 , wherein the reporter molecule is a rare earth element.
24. The method of claim 5 , further comprising at least one additional fractional initiator probe.
25. The method of claim 5 , wherein the target molecule is any nucleic acid molecule.
26. The method of claim 5 , wherein the target molecule is a protein.
27. The method of claim 5 , wherein the target molecule is selected from the group consisting of at least one of: mRNA, miRNA, lncRNA, rRNA, non-coding RNA, and genomic DNA.
28. The method of claim 5 , wherein the target molecule is comprised of an amino acid sequence.
29. The method of claim 5 , wherein the target molecule is comprised of a complex of molecules.
30. The method of claim 5 , wherein the first fractional initiator probe comprises a synthetic polymer and the second fractional initiator probe comprises a synthetic polymer.
31. The method of claim 5 , wherein the first fractional initiator probe comprises an amino acid sequence and the second fractional initiator probe comprises an amino acid sequence.
32. The method of claim 5 , wherein the first and second fractional initiators can base-pair with a first hairpin monomer.
33. The method of claim 5 , wherein the first fractional initiator probe comprises at least one molecule selected from the group consisting of DNA, RNA, 2′OMe-RNA, LNA, synthetic nucleic acid analog, amino acid, synthetic amino acid analog, and PNA and the second fractional initiator probe comprises at least one molecule selected from the group consisting of DNA, RNA, 2′Ome-RNA, LNA, synthetic nucleic acid analog, amino acid, synthetic amino acid analog, and PNA.
34. The method of claim 9 , wherein binding denotes hybridization.
35. The method of claim 9 , wherein binding denotes a selective protein-protein interaction.
36. The method of claim 9 , wherein binding denotes a selective nucleic acid-protein interaction.
37. A composition, comprising:
a first fractional initiator probe comprising:
a first target binding region and a first fractional initiator,
a second fractional initiator probe comprising:
a second target binding region and a second fractional initiator,
and a first hairpin monomer comprising:
a first input domain comprising a first toehold and a first stem section, and a first output domain comprising a first loop and a complement to the first stem section;
wherein the first and second target binding regions are capable of binding a target molecule so as to colocalize the first and second fractional initiators, and
wherein the colocalized first and second fractional initiators are capable of binding to the first input domain of the first hairpin monomer to open the first hairpin monomer and expose the first output domain.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 8, 2025
From: PIERCE, NILES A.; CHOI, HARRY M.T.
To: CALIFORNIA INSTITUTE OF TECHNOLOGY
Reel/Frame 072185/0161 →
Continuity (4)
Provisional Application
62358462
· Jul 5, 2016
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