Therapeutic Editing
Disclosed herein are compositions that comprise engineered polynucleotides, pharmaceutical compositions comprising the same, methods of making the same, and methods of treatment comprising the compositions that comprise the engineered polynucleotides.
1 . A composition that comprises: an engineered polynucleotide comprising a targeting sequence that is at least partially complementary to a region of a target RNA, wherein the region of the target RNA:
(a) comprises a sequence that at least partially encodes for an amyloid precursor protein (APP) polypeptide;
(b) comprises a sequence that is proximal to (a); or
(c) comprises (a) and (b); and wherein the engineered polynucleotide is configured to facilitate an editing of a base of a nucleotide of the target RNA by an RNA editing entity.
2 . The composition of claim 1 , wherein the editing of the base of the nucleotide of the target RNA by the RNA editing entity facilitates an increase or a decrease of:
(a) a processing;
(b) a cleavage; or
(c) (a) and (b),
of the APP polypeptide by a secretase enzyme, relative to an APP polypeptide encoded by the target RNA without the editing.
3 . The composition of claim 2 , wherein the secretase enzyme comprises: an alpha secretase; a beta secretase; a gamma secretase; or a combination thereof.
4 . The composition of claim 3 , wherein the secretase enzyme comprises the beta secretase, and wherein the beta secretase comprises beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), cathepsin B, or Meprin beta.
5 .- 32 . (canceled)
33 . The composition of claim 1 , wherein the nucleotide is comprised in a codon which encodes an amino acid in proximity to a cleavage site of the APP polypeptide, and wherein the amino acid is at position 670, 671, 672, 673, 682, 684, 687, 712, or 714 of the APP polypeptide comprising the polypeptide sequence of SEQ ID NO: 2.
34 .- 85 . (canceled)
86 . An engineered polynucleotide that comprises a sequence that comprises at least 90%, 95%, 97%, or 99% sequence identity with at least a portion of a sequence selected from: SEQ ID NO: 52, SEQ ID NO: 71-SEQ ID NO: 148, and SEQ ID NO: 159-SEQ ID NO: 167.
87 . An engineered polynucleotide that comprises a targeting sequence capable of at least partially binding to a sequence that comprises at least 90%, 95%, 97%, or 99% sequence identity with a portion of a sequence selected from: SEQ ID NO: 150-SEQ ID NO: 158 as determined by BLAST.