Abstract: Compositions and methods for editing deleterious mutations associated with Alpha-1 Antitrypsin Deficiency (A1AD). In particular embodiments, the invention provides methods for treating A1AD using a modified adenosine base editor with improved on-target editing and decreased off-target editing to correct mutations associated with A1AD.

Abstract: Compositions and methods for editing deleterious mutations associated with Alpha-1 Antitrypsin Deficiency (A1AD). In particular embodiments, the invention provides methods for treating A1AD using a modified adenosine base editor with improved on-target editing and decreased off-target editing to correct mutations associated with A1AD.

Abstract: This disclosure provides compositions and methods for the editing of a SERPINA1 gene with prime editing.

Abstract: Compositions and methods for reducing complement activation by introducing one or more alterations into a complement component 3 (C3) polynucleotide in a cell. In particular embodiments, the disclosure features a base editor system (e.g., a fusion protein or complex comprising a programmable DNA binding protein, a nucleobase editor, and gRNA) for modifying a C3 polynucleotide, where the modification is associated with reduced expression, and/or reduced activity of the C3 polypeptide encoded by the polynucleotide.

Abstract: The present invention provides, among other things, circular guide RNA (cgRNA) compositions and methods for making same. For example, in some aspects, a method of making egRN A is provided comprising enzymatically ligating two ends of a linear guide RNA, creating a cgRNA. In some aspects, a. method is provided for making cgRNA comprising contacting a linear guide RNA with a ligating enzyme, wherein the contacting brings together a first end and a second end of the guide RN A. and wherein the ligating enzyme ligates the first and the second end of the guide RNA thus creating a cgRNA. In some aspects, circularization is carried out by self-splicing introns. In some aspects, provided are circular RNA compositions, for example, circular messenger RNA, and methods for making same.

Abstract: The present invention provides, among other things, a guide RNA conjugated to a NLS sequence (NLS-gRNA) and method for making and using the same. For example, in some embodiments, the 3? end of the gRNA is conjugated to the N-terminus of a nuclear localization sequence (NLS) via a linker comprising a chemical moiety and a peptide spacer.

Abstract: Described and provided are adenosine base editors and compositions comprising adenosine base editors that have increased efficiency. Also described and provided are methods of using base editors comprising adenosine deaminase variants for altering mutations associated with Glycogen Storage Disease Type 1a (GSD1a).

Abstract: The present invention provides, among other things, a method of producing a synthetic RNA using a self-templating approach. For example, in some embodiments a synthetic gRNA is produced comprising: contacting a first RNA with a second RNA, wherein the first RNA and the second RNA comprise at least five RNA nucleotides that are complementary, and wherein the contacting forms a stem structure or a stem loop structure, and ligating the first RNA and the second RNA with a ligating enzyme (i) within the stem structure, or (ii) at an end of the stem structure, thereby forming a loop at the end of the stem structure.

Abstract: Provided herein are prime editing systems featuring prime editors complexed with a chimeric prime editing (PE) guide polynucleotide. Systems, prime editor fusion proteins and methods of using such editors for editing a double-stranded DNA target sequence are also provided.