US 11,713,470 B2
Targeted gene therapies for pain and other neuro-related disorders
Rebecca Seal, Pittsburgh, PA (US); and Cynthia Mary Arokiaraj, Pittsburgh, PA (US)
Assigned to University of Pittsburgh—Of the Commonwealth System of Higher Education, Pittsburgh, PA (US)
Appl. No. 16/493,387
Filed by University of Pittsburgh—Of the Commonwealth System of Higher Education, Pittsburgh, PA (US)
PCT Filed Mar. 20, 2018, PCT No. PCT/US2018/023364
§ 371(c)(1), (2) Date Sep. 12, 2019,
PCT Pub. No. WO2018/175443, PCT Pub. Date Sep. 27, 2018.
Claims priority of provisional application 62/473,630, filed on Mar. 20, 2017.
Prior Publication US 2020/0131537 A1, Apr. 30, 2020
Int. Cl. C12N 15/90 (2006.01); A61K 47/64 (2017.01); A61K 48/00 (2006.01); C07K 14/705 (2006.01); C12N 15/86 (2006.01); A61K 45/06 (2006.01)
CPC C12N 15/90 (2013.01) [A61K 47/6425 (2017.08); A61K 48/0075 (2013.01); C07K 14/705 (2013.01); C12N 15/86 (2013.01); A61K 45/06 (2013.01); C12N 2750/14143 (2013.01); C12N 2800/30 (2013.01); C12N 2830/008 (2013.01)] 5 Claims
 
1. A method of treating persistent pain in a patient comprising:
delivering to the dorsal horn of the spinal cord of the patient a nucleic acid comprising a gene for expressing a modified ligand-gated ion channel, comprising an open reading frame encoding a modified ligand-gated ion channel under transcriptional control of transcriptional control elements governing cell-specific expression in dorsal horn neurons, wherein the modified ligand-gated ion channel comprises a modified ligand binding domain activatable by an exogenous ligand, and an ion pore domain,
wherein the modified ligand-gated ion channel is a modified α7 nicotinic acetylcholine ligand binding domain comprising:
a. a L131G amino acid substitution, a Q139L amino acid substitution, and a Y217F amino acid substitution;
b. a W77F amino acid substitution, a Q79G amino acid substitution, and a G175K amino acid substitution;
c. a Q79G amino acid substitution, a Y115F amino acid substitution, and a G175K amino acid substitution;
d. a Y115F amino acid substitution and a G175K amino acid substitution;
e. a Q79G amino acid substitution and a P216I amino acid substitution; or
f. a R27D amino acid substitution and/or a E41R amino acid substitution,
wherein the transcriptional control element is a promoter sequence having at least 75% sequence identity with the sequence of one of SEQ ID NOs: 1-17,
wherein the ion pore domain is a GlyR ion pore domain comprising an A298G amino acid substitution; and
administering an exogenous ligand to the patient in an amount effective to activate the modified ligand gated ion channel in the patient, thereby treating the disease or disorder associated with the nervous system in the patient.