Provided herein are engineered transcription factors for selective upregulation of SCN1a and uses thereof for treating diseases and disorders, such as, Dravet syndrome. Also provided are microRNA binding sites and uses thereof for selective expression in parvalbumin neurons.

The present invention provides a novel fusion polypeptide containing a catalytic domain of NPP1 fused to a targeting moiety, nucleic acids encoding the fusion polypeptide, a vector containing the nucleic acid integrated thereinto, a host cell transformed with the vector and pharmaceutical compositions comprising the fusion polypeptide.

Aspects of the disclosure relate to compositions and methods for expressing one or more Ganglioside GM3 synthase (GM3S) isoforms in a cell or subject. In some aspects, the disclosure relates to methods for treating GM3 synthase deficiency in a subject in need thereof.

The disclosure features compositions or systems and uses thereof, comprising a first polynucleotide encoding a target molecule, optionally a second polynucleotide encoding an effector, repressor, or endonuclease molecule; optionally a recognition or cleavage site in the first or second polynucleotide, and optionally a repressor/effector binding site in the first polynucleotide. The disclosure also features compositions or systems and uses thereof, comprising a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) at least six miR142 target sites.

Provided herein are engineered transcription factors for selective upregulation of SCN1a and uses thereof for treating diseases and disorders, such as, Dravet syndrome. Also provided are microRNA binding sites and uses thereof for selective expression in parvalbumin neurons.

Nucleic acid molecules configured to specifically express a sequence of interest in a cancer cell, comprising: a transcription factor binding region comprising 3-10 repeats of a transcription factor binding site, a minimal promoter and the sequence of interest operatively linked to the transcription factor binding region and minimal promoter, wherein the transcription factor is selected from SOX9, GATA10, TCF7L1, LEF1, MYBL2 and MYB are provided. Nucleic acid molecule systems and compositions comprising the nucleic acid molecules are also provided as are methods of treating cancer.