IP Library › Granted Patent US 12,359,253
Granted Patent B2
US 12,359,253 · App. 17/045,734 · Granted Jul 15, 2025

Method of in situ gene sequencing

Inventors: Xiao Wang (Stanford, CA); William E. Allen (Albany, CA); Karl A. Deisseroth (Stanford, CA)
Assignee: The Board of Trustees of the Leland Stanford Junior University
C12Q1/6874C12Q1/6876C12Q2600/136C12Q2600/158
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Quick Facts
Patent No.
US 12,359,253
App. No.
17/045,734
Granted
Jul 15, 2025
Kind
B2
Abstract

Provided herein are devices, methods, and systems for in situ gene sequencing of a target nucleic acid in a cell in an intact tissue. Methods of screening a candidate agent to determine whether the candidate agent modulates gene expression of a nucleic acid in a cell in an intact tissue are also provided herein.

Claims (47)

1. A method for identifying a nucleic acid in a cell within a tissue, comprising:

(a) contacting the tissue with at least a pair of oligonucleotides under conditions to allow for specific hybridization of the pair of oligonucleotides to the nucleic acid, wherein the pair of oligonucleotide comprises:

(i) a first oligonucleotide, wherein the first oligonucleotide comprises a first complementarity region, a second complementarity region, and a third complementarity region; and

(ii) a second oligonucleotide, wherein the second oligonucleotide comprises a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region; and

wherein the first complementarity region is complementary to a first portion of the nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to the sixth complementarity region, the fifth complementarity region is complementary to a second portion of the nucleic acid, wherein the first complementarity region and fifth complementarity region are hybridized to the nucleic acid;

(b) performing an amplification reaction on the nucleic acid having the pair of oligonucleotides hybridized thereto to yield one or more amplicons, wherein the one or more amplicons are embedded in a hydrogel; and

(c) imaging the one or more amplicons to identify the nucleic acid.

2. The method of claim 1 , further comprising, subsequent to (b), clearing the tissue of a plurality of cellular components.

3. The method of claim 2 , wherein the cellular components comprise lipids, proteins, or any combination thereof.

4. The method of claim 1 , wherein the pair of oligonucleotides are denatured by heating before contacting the tissue.

5. The method of claim 1 , wherein the cell is present in a population of cells.

6. The method of claim 5 , wherein the population of cells comprises a plurality of cell types.

7. The method of claim 1 , wherein the tissue is fixed and permeabilized with a single solution.

8. The method of claim 1 , wherein the nucleic acid is ribonucleic acid (RNA).

9. The method of claim 1 , wherein the nucleic acid is messenger RNA.

10. The method of claim 1 , wherein the nucleic acid is DNA.

11. The method of claim 1 , wherein the second oligonucleotide is provided as a closed nucleic acid circle.

12. The method of claim 1 , wherein:

(i) the second oligonucleotide comprises a padlock probe,

(ii) the first complementarity region of the first oligonucleotide has a length of 19 nucleotides to 25 nucleotides,

(iii) the second complementarity region of the first oligonucleotide has a length of 3 nucleotides to 10 nucleotides,

(iv) the third complementarity region of the first oligonucleotide has a length of 3 nucleotides to 10 nucleotides,

(v) the fourth complementarity region of the second oligonucleotide has a length of 3 nucleotides to 10 nucleotides,

(vi) the fifth complementarity region of the second oligonucleotide has a length of 19 nucleotides to 25 nucleotides,

(vii) the sixth complementarity region of the second oligonucleotide has a length of 3 nucleotides to 10 nucleotides,

(viii) the fourth complementarity region of the second oligonucleotide comprises a 5′ end of the second oligonucleotide,

(ix) the sixth complementarity region of the second oligonucleotide comprises a 3′ end of the second oligonucleotide,

(x) the fourth complementarity region of the second oligonucleotide is adjacent to the sixth complementarity region of the second oligonucleotide or any combination thereof.

13. The method of claim 1 , wherein

(i) a third oligonucleotide is configured to decode bases; and

(ii) a fourth oligonucleotide is configured to convert the decoded bases into a signal.

14. The method of claim 1 , wherein the imaging comprises imaging the one or more amplicons that are embedded in hydrogel using a microscopy selected from the group consisting of confocal microscopy, widefield fluorescence microscopy, two-photon microscopy, light-field microscopy, intact tissue expansion microscopy, super-resolution microscopy, and light sheet microscopy.

15. The method of claim 14 , wherein the light sheet microscopy is CLARITY-optimized light sheet microscopy (COLM).

16. The method of claim 1 , wherein the tissue has a thickness of 5 micrometers (μm) to 20 μm.

17. The method of claim 1 wherein the tissue is a thick slice having a thickness of 5 μm to 200 μm.

18. A method of screening a candidate agent to determine whether the candidate agent modulates gene expression of the nucleic acid in the cell in the tissue, comprising: performing the method of claim 1 to determine gene sequencing of the nucleic acid in the cell in the tissue, and

detecting a level of gene expression of the nucleic acid, wherein an alteration in the level of gene expression of the nucleic acid in the presence of the candidate agent relative to the level of expression of the nucleic acid in the absence of the at least one candidate agent indicates that the at least one candidate agent modulates gene expression of the nucleic acid in the cell in the tissue.

19. The method of claim 18 , wherein the detecting comprises determining a signal.

20. The method of claim 19 , wherein the signal is a fluorescent signal.

21. The method of claim 1 , further comprising adding a ligase to ligate a first end of the second oligonucleotide to a second end of the second oligonucleotide thereby generating a closed nucleic acid circle.

22. The method of claim 21 , wherein the ligase is a DNA ligase.

23. The method of claim 1 , wherein the amplification reaction comprises rolling circle amplification, and wherein the second oligonucleotide is a template and the first oligonucleotide is a primer for a polymerase to form one or more amplicons.

24. The method of claim 1 , wherein the one or more amplicons is embedded in the hydrogel after the amplification reaction of (b).

25. The method of claim 1 , wherein the one or more amplicons is embedded in the hydrogel by copolymerizing the one or more amplicons with acrylamide.

26. The method of claim 1 , wherein the tissue is embedded in the hydrogel prior to (b).

27. The method of claim 1 , wherein the first portion of the nucleic acid and the second portion of the nucleic acid are separated by one or more nucleotides.

28. The method of claim 1 , wherein the first complementarity region is adjacent to the fifth complementarity region.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 7, 2020
From: DEISSEROTH, KARL
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 053998/0761 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 7, 2020
From: HOWARD HUGHES MEDICAL INSTITUTE
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 053998/0829 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 7, 2020
From: WANG, XIAO; ALLEN, WILLIAM E.
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 053998/0883 →
Continuity (4)
Provisional Application 62808159 · Feb 20, 2019
Provisional Application 62687490 · Jun 20, 2018
Provisional Application 62655052 · Apr 9, 2018
Related Publication 20210164039A1 · Jun 3, 2021
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