US 11,730,828 B2
Gene therapy for haploinsufficiency
Nadav Ahituv, San Francisco, CA (US); and Navneet Matharu, San Francisco, CA (US)
Assigned to The Regents of the University of California, Oakland, CA (US)
Appl. No. 16/479,177
Filed by The Regents of the University of California, Oakland, CA (US)
PCT Filed Feb. 7, 2018, PCT No. PCT/US2018/017186
§ 371(c)(1), (2) Date Jul. 18, 2019,
PCT Pub. No. WO2018/148256, PCT Pub. Date Aug. 16, 2018.
Claims priority of provisional application 62/455,988, filed on Feb. 7, 2017.
Prior Publication US 2019/0351074 A1, Nov. 21, 2019
Int. Cl. C07H 21/02 (2006.01); A61K 48/00 (2006.01); A61P 3/04 (2006.01); A01K 67/027 (2006.01); C12N 9/22 (2006.01); C12N 15/113 (2010.01); C12N 15/86 (2006.01); C12N 15/10 (2006.01)
CPC A61K 48/0066 (2013.01) [A01K 67/0276 (2013.01); A61K 48/0016 (2013.01); A61P 3/04 (2018.01); C12N 9/22 (2013.01); C12N 15/102 (2013.01); C12N 15/113 (2013.01); C12N 15/86 (2013.01); A01K 2217/077 (2013.01); A01K 2227/105 (2013.01); A01K 2267/0362 (2013.01); C12N 2310/20 (2017.05)] 8 Claims
 
1. A method of treating a haploinsufficiency disease in a mammalian subject, the method comprising contacting a cell of the subject with a composition comprising:
i) a catalytically inactive CRISPR nuclease fused to a transcriptional activation domain, and
ii) a guide RNA, wherein the guide RNA comprises:
a) a targeting region that, under conditions present in a nucleus of the cell, specifically hybridizes to a promoter region or an enhancer region operably linked to a wild-type copy of a haploinsufficient gene; and
b) a binding region that specifically binds the catalytically inactive CRISPR nuclease under conditions present in a nucleus of the cell,
wherein the contacting forms a complex comprising the catalytically inactive CRISPR nuclease bound to the guide RNA, wherein the targeting region of the guide RNA in the complex is hybridized to the promoter or enhancer of the wild-type copy of the haploinsufficient gene; and
wherein the complex activates transcription of the wild-type copy of the haploinsufficient gene in an amount and for a duration sufficient to treat the haploinsufficiency disease in the subject.