The invention provides compositions comprising novel programmable adenosine base editor systems (e.g., ABE8) that provide methods of treating a disease or disorder, (e.g., Parkinson's disease, Hurler syndrome, Rett syndrome, or Stargardt disease) in a subject by administering to the subject a programmable adenosine base editor system (e.g., ABE8) that have increased efficiency and methods of using these adenosine deaminase variants for editing a disease-associated gene.

The present disclosure provides use of adenosine deaminase (ADA) and an ADA modifier in preparation of a medicament for wound repair in a patient with diabetes. It is found for the first time that the ADA (EC 3.5.4.4) and a polyethylene glycol-modified adenosine deaminase (PEG-ADA) have a significant improvement effect on wound repair of type-2 diabetic mice, and the ADA or the ADA modifier can be developed into a medicament for treating diabetic wounds.

Provided are methods for using chimeric proteins to produce RNA modifications that can be detected by sequencing methods, including methods detecting relative translation rates of various mRNAs. Also provided herein are compositions comprising chimeric proteins, wherein the chimeric proteins comprise a RNA editing protein and a ribosomal protein.

Provided are variant adenosine deaminase 2 (ADA2) proteins, conjugates thereof and compositions containing the proteins and/or conjugates. Also provided are methods and uses of the ADA2 proteins or conjugates for treating diseases and conditions, such as a tumor or cancer, and in particular any disease or condition associated with elevated adenosine or other associated marker.

The disclosure provides for systems, methods, and compositions for targeting and editing nucleic acids. In particular, the invention provides non-naturally occurring or engineered RNA-targeting systems comprising a RNA-targeting Cas13 protein, at least one guide molecule, and at least one adenosine deaminase protein or catalytic domain thereof.

A method of treating an inherited retinal disease (IRD) associated with a pathogenic point mutation in a mutant allele of an IRD-related gene in the retina or the retinal pigment epithelium (RPE) of a subject in need thereof includes base editing the pathogenic point mutation in the retinal cell or retinal pigment epithelium cell to correct the pathogenic mutation, generate a non-pathogenic point mutation, or modulate expression of an IRD-related gene and restore visual function of subject.

Some aspects of this disclosure provide strategies, systems, reagents, methods, and kits that are useful for the targeted editing of nucleic acids, including editing a single site within the genome of a cell or subject, e.g., within the human genome. In some embodiments, fusion proteins of Cas9 and nucleic acid editing enzymes or enzyme domains, e.g., deaminase domains, are provided. In some embodiments, methods for targeted nucleic acid editing are provided. In some embodiments, reagents and kits for the generation of targeted nucleic acid editing proteins, e.g., fusion proteins of Cas9 and nucleic acid editing enzymes or domains, are provided.

Provided herein are compositions and methods for detection of N.sup.6-methyladenosine (m.sup.6A) in ribonucleic acid (RNA). The provided compositions include fusion proteins that can be used to edit RNA and detect m6A residues. Also provided are nucleic acids, vectors, constructs, host cells, and transgenic animals that encode or express such fusions proteins.

The present invention features compositions and methods for editing deleterious mutations associated with hemoglobinopathies, such as sickle cell disease (SCD). In particular embodiments, the invention provides methods for correcting mutations in a beta globin polynucleotide using modified adenosine base editors termed “ABE8” having unprecedented levels (e.g., >60-70%) of efficiency.

The present disclosure provides genome engineering proteins, e.g., nucleic acid binding domains and/or functional domains that have a net positive charge and are cell permeable and can be introduced into the cells without the use of a carrier such as micelles, vesicles, liposomes, and the like.