TISSUE SELECTIVE TRANSGENE EXPRESSION
Provided herein are compositions and methods for selective expression of a transgene. Compositions and methods for selective expression of a transgene comprise one or more human regulatory elements, which, when operably linked to a transgene, can facilitate selective expression of a transgene (e.g., cell-type selective expression) in a target cell as compared to at least one or more non-target cells.
1 . A viral vector comprising a regulatory element operably linked to a transgene, wherein the regulatory element results in selective expression in the CNS such that at least 40% of CNS cells expressing the transgene are parvalbumin (PV) neurons.
2 . The viral vector of claim 1 , wherein at least 50% of CNS cells expressing the transgene are PV neurons.
3 . The viral vector of claim 2 , wherein at least 60% of CNS cells expressing the transgene are PV neurons.
4 . The viral vector of claim 3 , wherein at least 65% of CNS cells expressing the transgene are PV neurons.
5 . The viral vector of claim 4 , wherein at least 70% of CNS cells expressing the transgene are PV neurons.
6 . The viral vector of claim 1 , wherein the transgene comprises a nucleic acid sequence encoding a DNA binding protein.
7 . The viral vector of claim 6 , wherein the DNA binding protein is a transcriptional modulator of an endogenous gene.
8 . The viral vector of claim 6 , wherein the DNA binding protein comprises a zinc finger.
9 . The viral vector of claim 6 , wherein the DNA binding protein is linked to a transcriptional activator domain.
10 . The viral vector of claim 6 , wherein the DNA binding protein is linked to a transcriptional repressor domain.
11 . The viral vector of claim 6 , wherein the DNA binding protein is a transcriptional activator that modulates an endogenous SCN1A gene.
12 . The viral vector of claim 1 , wherein the transgene comprises a gene editing protein.
13 . The viral vector of claim 12 , wherein the gene editing protein is a Cas protein.
14 . The viral vector of claim 1 , wherein the regulatory element is human derived.
15 . The viral vector of claim 14 , wherein the regulatory element has at least 90% sequence identity with a human genomic sequence.
16 . The viral vector of claim 15 , wherein the regulatory element has at least 95% sequence identity with a human genomic sequence.
17 . The viral vector of claim 1 , wherein the viral vector is an adeno-associated virus (AAV) vector.
18 . The viral vector of claim 17 , wherein the AAV vector is AAV1, AAV8, AAV9, scAAV1, scAAV8, or scAAV9.
19 . The viral vector of claim 18 , wherein the AAV vector is AAV9.
20 . The viral vector of claim 18 , wherein the AAV vector is scAAV9.
21 . The viral vector of claim 1 , wherein the viral vector is a lentiviral vector.
22 . The viral vector of claim 1 , wherein the percent of CNS cells expressing the transgene that are PV neurons is measured by a co-localization assay.
23 . The viral vector of claim 22 , wherein the co-localization assay is an immunohistochemical assay.
24 . The viral vector of claim 23 , wherein the immunohistochemical assay comprises an anti-PV antibody.
25 . The viral vector of claim 1 , wherein the regulatory element has a total length of 500 bp-1500 bp.
26 . The viral vector of claim 1 , wherein the regulatory element is less than 2.5 kb in size.
27 . The viral vector of claim 26 , wherein the regulatory element is less than 1.5 kb in size.
28 . The viral vector of claim 27 , wherein the regulatory element is less than 1 kb in size.
29 . The viral vector of claim 17 , wherein the viral vector further comprises a 5′ AAV inverted terminal repeat (ITR) sequence and a 3′ AAV ITR sequence.
30 . The viral vector of claim 29 , wherein the ITR sequences are AAV2 ITR sequences.