IP Library › Granted Patent US 12692515
Granted Patent B2
US 12692515 · App. 18/000,574 · Granted Jul 28, 2026

Artificial expression constructs for selectively modulating gene expression in inhibitory neocortical neurons

Inventors: Tanya Daigle (Lake Forest Park, WA); Lucas T. Graybuck (Seattle, WA); Edward Sebastian Lein (Mercer Island, WA); Boaz P. Levi (Seattle, WA); John K. Mich (Seattle, WA); Adriana Estela Sedeño Cortés (Seattle, WA); Bosiljka Tasic (Seattle, WA); Jonathan Ting (Lake Forest Park, WA); Miranda Walker (Ann Arbor, MI); Hongkui Zeng (Seattle, WA)
Assignee: Allen Institute
C12N15/86A61K9/0019A61K9/0085C12N15/11C12N2510/02C12N2750/14141
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Quick Facts
Patent No.
US 12692515
App. No.
18/000,574
Granted
Jul 28, 2026
Kind
B2
Abstract

Artificial expression constructs for selectively modulating gene expression in selected central nervous system cell types are described. The artificial expression constructs can be used to selectively express synthetic genes or modify gene expression in inhibitory neocortical GABAergic neurons including somatostatin GABAergic neurons, parvalbumin GABAergic neurons, vasointestinal peptide GABAergic neurons, Lamp5 GABAergic neurons, and in some instances astrocytes.

Claims (21)

1 . An artificial expression construct comprising (i) an enhancer selected from SEQ ID NO: 11, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 166, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 163, and SEQ ID NO: 165 or a sequence having at least 95% sequence identity to the sequence as set forth in any of SEQ ID NOs: 1-25, 132-166; (ii) a promoter; and (iii) a heterologous encoding sequence.

2 . The artificial expression construct of claim 1 , wherein the heterologous encoding sequence encodes a fluorescent protein.

3 . The artificial expression construct of claim 1 , wherein the heterologous encoding sequence encodes a neurotransmitter.

4 . The artificial expression construct of claim 1 , wherein the artificial expression construct is associated with a capsid that crosses the blood brain barrier.

5 . The artificial expression construct of claim 4 , wherein the capsid comprises PHP.eB, AAV9, AAVrh.10, AAV-BR1, AAV-PHP.S, AAV-PHP.B, or AAV-PPS.

6 . The artificial expression construct of claim 1 , wherein the artificial expression construct includes or encodes a skipping element.

7 . The artificial expression construct of claim 6 , wherein the skipping element comprises a T2A peptide, P2A peptide, E2A peptide, F2A peptide, or an internal ribosome entry site (IRES).

8 . The artificial expression construct of claim 1 , wherein the artificial expression construct is within a viral vector.

9 . The artificial expression construct of claim 8 , wherein the viral vector comprises a recombinant adeno-associated viral (AAV) vector.

10 . A method for selectively expressing a heterologous encoding sequence within a population of cells in vivo or in vitro, the method comprising providing an administrable composition comprising an artificial expression construct, wherein the artificial expression construct comprises (i) and enhancer having a sequence as set forth in SEQ ID NO: 11, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 166, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 163, and SEQ ID NO: 165 or a sequence having at least 95% sequence identity to the sequence as set forth in any of SEQ ID NOs: 1-25, 132-166; (ii) a promoter; and (iii) a heterologous encoding sequence

in a sufficient dosage and for a sufficient time to a sample or subject comprising the population of cells thereby selectively expressing the heterologous encoding sequence within the population of cells.

11 . The method of claim 10 , wherein the heterologous encoding sequence encodes a fluorescent protein or a neurotransmitter.

12 . The method of claim 10 , wherein the providing comprises pipetting to a brain slice.

13 . The method of claim 12 , wherein the brain slice comprises an Sst GABAergic neuron, a Pvalb GABAergic neuron, a Pvalb/Sst GABAergic neuron, a Vip GABAergic neuron, a Lamp5 GABAergic neuron, and/or an astrocyte.

14 . The method of claim 12 , wherein the brain slice comprises a Lamp5_Lhx6 GABAergic neuron.

15 . The method of claim 10 , wherein the providing comprises administering to a living subject.

16 . The method of claim 15 , wherein the living subject is a human, non-human primate, or a mouse.

17 . The method of claim 15 , wherein the administering to a living subject is through injection.

18 . The method of claim 17 , wherein the injection comprises intravenous injection, intraparenchymal injection into brain tissue, intracerebroventricular (ICV) injection, intra-cisterna magna (ICM) injection, or intrathecal injection.

19 . An artificial enhancer comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 copies of a sequence as set forth in SEQ ID NO: 161, SEQ ID NO: 163, or SEQ ID NO: 165 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 161, SEQ ID NO: 163, or SEQ ID NO: 165.

20 . The artificial enhancer of claim 19 , comprising the sequence as set forth in SEQ ID NO: 162, SEQ ID NO: 164, or SEQ ID NO: 166 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 162, SEQ ID NO: 164, or SEQ ID NO: 166.