Granted Patent
B2
US 12,442,020 · App. 17/959,089 · Granted Oct 14, 2025
Materials and methods for treatment of pain related disorders
Inventors:
Ante Sven Lundberg (Cambridge, MA); Samarth Kulkarni (Cambridge, MA); Lawrence Klein (Cambridge, MA); Hari Kumar Padmanabhan (Cambridge, MA)
Assignee:
Vertex Pharmaceuticals Incorporated
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Abstract
The present application provides materials and methods for treating a patient with one or more conditions associated with SCN9A whether ex vivo or in vivo. In addition, the present application provides materials and methods for editing and/or modulating the expression of SCN9A gene in a cell by genome editing.
Claims (21)
1. A method for editing a Sodium Voltage-Gated Channel Alpha Subunit 9 (SCN9A) gene in a cell by genome editing comprising: introducing into the cell (a) one or more S. pyogenes Cas9 (spCas9) endonuclease or one or more polynucleotide encoding the one or more spCas9 endonuclease and (b) one or more gRNA or sgRNA or one or more nucleic acid encoding the one or more gRNA or sgRNA, wherein the one or more gRNA or sgRNA comprises a spacer sequence that targets a sequence within or near the SCN9A gene to effect one or more single-strand breaks (SSBs) or double-strand breaks (DSBs) within or near the SCN9A gene or SCN9A regulatory elements that results in one or more permanent insertions, deletions or mutations of at least one nucleotide within or near the SCN9A gene, thereby reducing or eliminating the expression or function of SCN9A gene products, wherein the spacer sequence of the one or more gRNA or sgRNA is about 20 to 60 nucleotides in length and comprises an RNA sequence corresponding to any one of SEQ ID NO: 46832, 49122, 49431, 47474, 47446, 28779, 29821, 28146, 49436, 47224, 47462, 47240, 27323, 27522, 27893, 47261, 28137, 49367, 47232, 47445, 49313, 47267, 30622, 47231, 26766, 28139, 46079, 48091, 46833, 26765, 27876, 47241, 47248, 30051, 30111, 28760, 28085, 27254, 30163, 49303, 28083, 49344, 47245, 48090, 28132, 27328, 46078, 28773, 46496, 27885, 29928, 27933, 46039, 47439, 28774, 47455, 30020, 47236, 28089, 26813, 47464, 28091, 29908, 27892, 28776, 28783, 27252, 29930, or 47625.
2. The method of claim 1 , wherein the one or more spCas9 endonuclease comprises one or more nuclear localization signal (NLS) or the one or more polynucleotide encoding the one or more spCas9 endonuclease further encodes one or more NLS.
3. The method of claim 2 , wherein the one or more NLS is at or within 50 amino acids of the amino-terminus of the spCas9 endonuclease and/or the one or more NLS is at or within 50 amino acids of the carboxy-terminus of the spCas9 endonuclease.
4. The method of claim 1 , wherein one or more spCas9 endonuclease is introduced into the cell.
5. The method of claim 1 , wherein the one or more polynucleotide encoding the one or more spCas9 endonuclease is codon optimized.
6. The method of claim 1 , wherein the one or more polynucleotide encoding the one or more spCas9 endonuclease is one or more DNA.
7. The method of claim 1 , wherein the one or more polynucleotide encoding the one or more spCas9 endonuclease is one or more RNA.
8. The method of claim 7 , wherein the one or more RNA is chemically modified.
9. The method of claim 1 , wherein said one or more gRNA or sgRNA is pre-complexed with the one or more spCas9 endonuclease.
10. The method of claim 1 , wherein the one or more spCas9 endonuclease or the one or more polynucleotide encoding the one or more spCas9 endonuclease and/or the one or more gRNA or sgRNA or the one or more nucleic acid encoding the one or more gRNA or sgRNA is formulated in a liposome or lipid nanoparticle.
11. The method of claim 1 , wherein the one or more polynucleotide encoding the one or more Cas9 endonuclease and/or the one or more nucleic acid encoding the one or more gRNA or sgRNA is provided by an AAV vector particle.
12. The method of claim 11 , wherein the AAV vector particle is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9 particle.
13. The method of claim 1 , wherein the cell is a stem cell.
14. The method of claim 13 , wherein the stem cell is a pluripotent stem cell, an induced pluripotent stem cell (iPSC), a mesenchymal stem cell, an adult stem cell, or a somatic stem cell.
15. The method of claim 1 , wherein the cell is a somatic cell.
16. The method of claim 15 , wherein the somatic cell is a neuron of the peripheral nervous system.
17. An ex vivo method for treating a patient having an SCN9A related condition or disorder comprising:
(a) editing a patient specific induced pluripotent stem cell (iPSC) or a mesenchymal stem cell according to the method of claim 1 to form an edited cell; and
(b) differentiating the edited cell of (a) into a neuron of the peripheral nervous system; and
(c) administering the neuron of the peripheral nervous system to the patient.
18. An in vivo method for treating a patient with an SCN9A related disorder comprising: editing the Sodium Voltage-Gated Channel Alpha Subunit 9 (SCN9A) gene in a cell of the patient according to the method of claim 1 , optionally wherein the cell is a neuron of the peripheral nervous system.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 3, 2023
From: LUNDBERG, ANTE SVEN; KULKARNI, SAMARTH; KLEIN, LAWRENCE; PADMANABHAN, HARI KUMAR
To: CRISPR THERAPEUTICS AG
Reel/Frame 062584/0658 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 3, 2023
From: CRISPR THERAPEUTICS AG
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 062584/0745 →
Continuity (4)
Continuation
16315547
Provisional Application
62461874
· Feb 22, 2017
Provisional Application
62358763
· Jul 6, 2016
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